Avoiding Acyclovir Neurotoxicity in Patients with Chronic Renal Failure Undergoing Haemodialysis

Prospective pharmacokinetic study

N= 7

To evaluate the pharmacokinetics of oral acyclovir in dialysis-dependent patients and propose a modified dosing regimen to prevent neurotoxicity

Patients established on unit-based haemodialysis with a dialysis duration of 4-6 hours, interdialytic period of 48 hours, oliguric renal failure (<200mL urine/day), no previous exposure to acyclovir, and no history of neuro/psychiatric symptoms

Not specified

Following routine haemodialysis, each patient received a single 800 mg tablet of acyclovir. Plasma acyclovir levels were monitored over 48 hours, including before and after the next dialysis. Pharmacokinetic parameters were estimated using computer modeling to predict serum levels from varying maintenance and loading doses.

Primary: Plasma acyclovir concentration levels

Secondary: Pharmacokinetic parameters such as half-life, clearance, and volume of distribution

All patients (n= 7)

All patients (n= 7)

Mean acyclovir concentration, µM

After 1 h

After 2 h

After 3 h

After 5 h

After 18 h

After 24 h

After 48 h (before next HD)

3.10

9.27

12.54

11.13

6.29

4.66

2.21

Elimination half-life, h (range)

Clearance, mL/min (range)

Vd, L (range)

20.2 (10.0-42.8)

206.5 (120.6-341.4)

334.2 (190.2-532.8)

Acyclovir removal via hemodialysis is efficient, removing approximately 51-60% of the drug. Based on pharmacokinetic modeling, administration of oral acyclovir at 200 mg twice daily (12-hourly) with loading doses of 400 or 800 mg predicts steady-state plasma concentrations averaging around 6.4 ± 0.8 µM, with higher loading doses (800 mg) associated with supratherapeutic plasma levels (~12.2 ± 2 µM). These elevated concentrations approach or exceed the threshold associated with neurotoxicity (reported as 12–34 µM), a well-documented adverse effect in patients with renal impairment.

A modified dosing regimen of acyclovir, with a loading dose of 400 mg and a maintenance dose of 200 mg twice daily, is sufficient to maintain therapeutic plasma levels and prevent neurotoxicity in dialysis-dependent patients. A further loading dose after dialysis is recommended to replace the drug removed during dialysis.

Impact of continuous hemodiafiltration on serum acyclovir concentrations in a patient with encephalopathy

Design

Case report

Case presentation

This clinical case involves a Japanese woman in her 70s with a complex medical history including renal failure, hypertension, hyperlipidemia, reflux esophagitis, chronic gastritis, and chronic bronchitis. Her regular medications were amlodipine, lansoprazole, rebamipide, atorvastatin, epinastine, and ambroxol, and her body weight was 66.2 kg.

The patient was treated with valacyclovir at 1000 mg TID for herpes zoster ophthalmicus, starting eight days before hospital admission. After seven days of valacyclovir therapy, she developed neurological symptoms including fever, dysarthria, altered consciousness, hallucinations, and headache, leading to admission to a local hospital. Her laboratory tests showed a marked decline in renal function, with serum creatinine escalating to 4.02 mg/dL and estimated creatinine clearance dropping to 12.9 mL/min, indicating acute kidney injury.

Based on clinical suspicion of varicella-zoster virus (VZV) encephalitis, intravenous acyclovir (ACV) was initiated. However, after three days without neurological improvement and with worsening renal impairment, the patient was transferred to a tertiary care emergency unit. Upon admission (Day 0), ACV-induced nephropathy and encephalopathy were strongly suspected. Consequently, ACV was discontinued, and continuous hemodiafiltration (CHDF) was initiated to enhance drug clearance.

Laboratory analysis on admission revealed elevated serum creatinine consistent with acute renal failure. Cerebrospinal fluid (CSF) analysis via lumbar puncture showed normal cell counts and protein levels, with negative polymerase chain reaction (PCR) tests for VZV and herpes simplex virus, and negative antibody titers (IgM and IgG). Additionally, the FilmArray meningitis/encephalitis panel detected no pathogens, ruling out active infectious encephalitis.

Measurement of serum ACV concentrations revealed toxic levels at 14.1 μg/mL, exceeding the neurotoxic threshold of 3.4 μg/mL. The pharmacokinetics of ACV in this patient were characterized by an extended elimination half-life of 19.5 hours due to end-stage renal disease. Following initiation of CHDF, serum ACV levels declined rapidly, supporting the efficacy of CHDF in clearing ACV and mitigating toxicity.

The clinical course demonstrated progressive improvement in consciousness, as indicated by rising Glasgow Coma Scale (GCS) scores concurrent with declining ACV concentrations during CHDF treatment. CHDF was discontinued on Day 3, and the patient showed no evidence of ongoing VZV infection, with no need to restart antiviral therapy. She was discharged on Day 17 without neurological sequelae or VZV relapse.

Study Author Conclusions

This case underlines the importance of cautious use of renally-excreted antivirals like valacyclovir and acyclovir in elderly patients with pre-existing renal impairment and comorbidities such as hypertension and female sex, which are recognized risk factors for ACV-induced nephrotoxicity. It highlights the need for careful renal function monitoring and dosage adjustment to prevent accumulation and neurotoxicity. The rapid reduction of ACV serum levels and neurological recovery with CHDF emphasize continuous hemodiafiltration as an effective intervention in cases of ACV overdose or toxicity in patients with compromised renal function.

Furthermore, alternative therapies which do not require renal dose adjustment may be considered in similar clinical scenarios, although their CSF penetration and potential adverse effects warrant consideration. This clinical experience adds valuable insight into the pharmacokinetics and management of ACV neurotoxicity in patients with renal dysfunction, supporting vigilant therapeutic drug monitoring and tailored renal replacement strategies to optimize patient outcomes.

Manic symptoms caused by acyclovir in a hemodialysis patient

Design

Case presentation

The case involves a 59-year-old male patient with end-stage renal disease (ESRD) who has been undergoing hemodialysis (HD) since the age of 53. His baseline premorbid condition was described as modest and quiet. The patient developed an infectious condition characterized by pain, papules, and blisters localized to the left facial area in a distribution consistent with the trigeminal nerve. Clinical diagnosis by a dermatologist confirmed herpes zoster virus infection, supported by elevated herpes zoster virus antibody titers in the blood.

The patient was promptly initiated on oral acyclovir at a dose of 15 mg/kg/day. However, after two days of therapy, he exhibited an abrupt neuropsychiatric deterioration, marked by restlessness, talkativeness, irritability, hyperkinesis, flight of ideas, and delusions of grandeur, all indicative of manic symptoms. Consciousness remained clear throughout this psychiatric episode.

On hospital admission, no significant laboratory abnormalities were noted outside those expected in ESRD patients, including elevated BUN (82.3 mg/dL) and creatinine (13.5 mg/dL). Cerebrospinal fluid analysis was unremarkable and did not demonstrate herpes zoster virus antibodies, effectively ruling out central nervous system viral involvement.

Acyclovir was discontinued on the third hospital day. Manic symptoms persisted for an additional three days before gradually resolving. Blood concentrations of acyclovir were measured using high-performance liquid chromatography, revealing supratherapeutic levels: 10.9 μg/mL on day 2, decreasing to 3.0 μg/mL before HD and 1.0 μg/mL after HD on day 4. The normal therapeutic range for acyclovir plasma concentration is 2.02-2.30 μg/mL, indicating significant drug accumulation prior to HD.

Study Author Conclusions

This case highlights the risk of neurotoxicity and manic symptoms associated with acyclovir in patients with ESRD on hemodialysis. The impaired renal clearance likely resulted in drug accumulation and consequent central nervous system adverse effects. Hemodialysis partially reduced acyclovir plasma levels but did not prevent symptom onset. Clinicians should exercise caution with acyclovir dosing in ESRD patients, considering dose adjustments or alternative antiviral agents to mitigate neuropsychiatric toxicity. Close monitoring for neurotoxic symptoms and therapeutic drug monitoring may be warranted when using acyclovir in this population.

A Case Report of Neurotoxicity After Prolonged Doses of Acyclovir in a Patient With Renal Dysfunction

Design

Case presentation

A 57-year-old male with multiple significant comorbidities (including end-stage renal disease [ESRD] on hemodialysis, type 2 diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, congestive heart failure, and a history of shingles and recurrent thigh abscesses) presented initially with a classic dermatomal vesicular rash diagnosed as herpes zoster. He was prescribed a full-dose oral acyclovir regimen 800 mg five times daily for 10 days and discharged from the emergency department.

Four days later, the patient was readmitted due to worsening symptoms including multiple episodes of diarrhea and signs of right thigh cellulitis and myositis with early abscess formation on MRI, alongside persistent herpes zoster lesions on the chest wall. The patient’s home oral acyclovir was resumed along with supportive care and continued thrice-weekly hemodialysis.

During hospitalization, the patient’s antiviral therapy was escalated to include intravenous acyclovir dosed at 5 mg/kg once, administered with concurrent oral dosing. This transition was followed by the emergence of neurological symptoms starting approximately five hours post IV dose, including dizziness, mild lethargy, slowed verbal response, progressing over the next days to disorientation, altered mentation, and myoclonic movements. These clinical manifestations raised high suspicion for acyclovir-induced neurotoxicity, particularly in the context of his ESRD, which significantly impairs drug clearance and predisposes to accumulation.

Extensive work-up including brain imaging (CT, MRI), EEG, and lumbar puncture with CSF analysis was performed to exclude infectious or malignant causes of encephalopathy. CSF studies showed lymphocytic predominance without evidence of viral infection by PCR, and other infectious panels were negative. Acyclovir serum levels drawn approximately 18 hours after dosing and following hemodialysis were elevated (8.5 mmol/L), consistent with accumulation and toxicity.

The management included holding intravenous acyclovir, continuation of hemodialysis, and close neurological monitoring. The patient’s altered mental status and myoclonic activity gradually improved by day 8 and resolved fully by day 9, with neurological examination returning to baseline. The herpes zoster lesions were noted to be healing well. The patient was subsequently discharged to a skilled nursing facility with planned outpatient follow-up.

Study Author Conclusions

This case exemplifies the critical importance of modifying antiviral dosing in patients with renal impairment, given acyclovir’s primary renal excretion and narrow therapeutic window. In this patient, full-dose oral acyclovir (800 mg five times daily) was administered for six days without renal dose adjustments. Despite the relatively low oral bioavailability of acyclovir (10–20%), the combination of prolonged therapy and decreased renal clearance likely resulted in elevated systemic levels and neurotoxicity. Notably, the onset of toxicity occurred eight days after initiation, which is slightly delayed compared to previous reports typically noting onset within five days. This delay may be attributed to the low bioavailability of the oral form and the intermittent hemodialysis session two days prior, which would have partially cleared the drug. Administration of an intravenous acyclovir dose on day five, adjusted for renal impairment and with higher bioavailability, likely exacerbated neurological symptoms.

Serum acyclovir levels in patients experiencing neurotoxicity exhibit wide variability, ranging from 1.12 to 295 mmol/L with a mean around 80.8 mmol/L. The patient's level was measured at 8.5 mmol/L, which falls on the lower end, but this sample was drawn 31 hours post-hemodialysis and 18 hours after the last dose, suggesting pre-dialysis levels would have been significantly higher. Importantly, neurotoxicity can manifest despite subtherapeutic or moderate serum levels due to the delayed correlation between peak concentrations and clinical symptoms, which may appear 24–48 hours after peak levels.

Hemodialysis effectively removes acyclovir; approximately 45–60% of the drug can be cleared during sessions lasting 3 to 6 hours. In this case, elevated post-dialysis acyclovir levels helped confirm drug-induced neurotoxicity as the etiology. Although the patient was concurrently on other neurotoxic risk medications such as cefepime and metronidazole, both were dosed appropriately for renal function and discontinued without symptom resolution, reinforcing acyclovir as the culprit.

Clinical improvement correlated with cessation of acyclovir and completion of two hemodialysis sessions, consistent with prior reports showing neurological recovery with drug discontinuation and enhanced clearance. This case underscores the critical importance of renal dose adjustment for acyclovir to prevent neurotoxicity, especially in ESRD patients.