Aciclovir

Observational studies

In a patient satisfaction questionnaire during a comparison of once- and twice-daily oral suppressive therapy with aciclovir for genital herpes, adverse effects were rarely reported [ ].

Comparative studies

The effects of aciclovir and valaciclovir for anogenital herpes have been studied in HIV-infected individuals in two controlled trials [ ]. In the first study, 1062 patients with CD4 + counts over 100 × 10 ⁶ /l received valaciclovir or aciclovir for 1 year and were assessed monthly. In the second study, 467 patients were treated episodically for at least 5 days with valaciclovir or aciclovir and were assessed daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpesvirus infections. Hazard ratios for the time to recurrence with valaciclovir 500 mg bd and 1000 mg od compared with aciclovir were 0.73 (95% CI = 0.50, 1.06) and 1.31 (0.94, 1.82). Valaciclovir 1000 mg bd and aciclovir had similar effects on the duration of infective episodes (HR = 0.92; CI = 0.75, 1.14). The most common adverse events, which occurred at similar rates with all regimens, were diarrhea, headache, infections, rashes, nausea, rhinitis, pharyngitis, abdominal pain, fever, depression, and cough.

Nervous system

Neurotoxicity secondary to aciclovir is rare and is associated with high plasma concentrations [SEDA-18, 299], such as result from impaired renal function [ ]. Although the risk is greatest with intravenous administration, neurotoxicity has previously been noted with oral use.

Symptoms of neurotoxicity, which usually appear within the first 24–72 hours of administration, include tremor, myoclonus, confusion, lethargy, agitation, hallucinations, dysarthria, asterixis, ataxia, hemiparesthesia, and seizures. While aciclovir-induced neurotoxicity is most prevalent with intravenous administration, it has also been reported after oral use in patients with terminal renal insufficiency on hemodialysis.

Neurotoxicity possibly secondary to the topical use of aciclovir has also been described [ ].

• A 59-year-old woman on hemodialysis was treated with oral aciclovir 200 mg/day for ophthalmic Herpes zoster . After a few days, an ophthalmic aciclovir cream was started (one application every 6 hours) because of ipsilateral Herpes keratitis. After 1 week of combined oral and topical treatment, she became confused, with dysarthria and audiovisual hallucinations. Aciclovir was withdrawn and hemodialysis was initiated. Complete resolution of symptoms was achieved after three hemodialysis sessions in 3 days. Aciclovir plasma concentrations before hemodialysis were high (45 μmol/l) and fell rapidly during hemodialysis.

There is no conclusive evidence for the contribution of the topically administered aciclovir to the high plasma concentrations and subsequent neurotoxicity in this case. However, the authors argued that the existence of high aciclovir plasma concentrations, in spite of careful adjustment of the oral dosage, pointed to significant topical absorption of the drug, especially since the absorption of aciclovir through the skin and mucous membranes may be unpredictable.

Coma has been attributed to oral aciclovir [ ].

• A 73-year-old man with acute respiratory failure, presumed to be secondary to amiodarone toxicity, developed sepsis and acute renal insufficiency, and required intermittent hemodialysis. Following a Herpes simplex labialis infection he was treated with oral acyclovir (400 mg tds). The next day he became sleepy, disoriented, and agitated. Over the next 48 hours his neurological condition deteriorated and he responded to pain only, had uncoordinated eye movements, tremors, facial and jaw myoclonus, increased reflexes, and hypertonia. After 7 days of aciclovir he became unresponsive and comatose. Aciclovir was withdrawn and hemodialysis carried out more frequently. His neurological status improved over a period of 4 days. Trough plasma concentrations of aciclovir were well above the upper limit of the usual target range.

This appears to be the first case of coma attributable to oral aciclovir. The fact that the patient was receiving oral rather than intravenous aciclovir and was on regular hemodialysis made neurotoxicity unlikely, and this emphasizes the need to be wary of this potentially serious complication in seriously ill elderly patients.

It has been suggested that hemodialysis can be a useful diagnostic tool in the differential diagnosis between aciclovir-induced neurotoxicity and herpes encephalitis, as well as a fast and reliable treatment of drug-induced neurotoxicity [ ].

• A previously healthy 59-year-old woman developed right eye pain for 3 days and vesicle formation on her forehead. She received intravenous aciclovir 250 mg every 8 hours, but 48 hours later she became drowsy and lethargic, with incoherent speech and hallucinations. Her blood urea nitrogen concentration rose from 0.71 mmol/l on admission to 2.41 mmol/l, serum creatinine rose from 53.6 to 442 (reference range 51–115) μmol/l and the serum sodium concentration fell from 135 to 121 mmol/l. Electroencephalography showed mild diffuse cortical dysfunction, with more emphasis in the right hemisphere, and regional epileptiform activity in the bilateral frontal and right parietal regions. An MRI scan of her head was normal. Because of deteriorating renal function and the debilitating nature of the neurological symptoms, which were thought to be due to acyclovir toxicity, hemodialysis was initiated. The pre-hemodialysis trough plasma aciclovir concentration was 18 mg/l, compared with peak and trough concentrations of 5.5–13.8 mg/l and 0.2–1 mg/l respectively in adults who receive 5 mg/kg of acyclovir [ ]. She underwent two 4-hour sessions of hemodialysis over 2 days. The post-hemodialysis plasma aciclovir concentration fell to 3 mg/l. Her conscious level improved and the blood urea nitrogen and serum creatinine concentrations fell to 6.1 mmol/l and 142 μmol/l respectively. She was well by the fifth day.

Reversible neurotoxicity in a 6-month old child after liver transplantation has been reported [ ].

• A 6-month-old girl had liver transplantation after liver failure secondary to an enterovirus infection, followed by initial immunosuppression with antilymphocyte serum, azathioprine, and glucocorticoids. Her renal function improved on day 3, and the antilymphocyte serum was switched to ciclosporin 10 mg/kg/day. Antimicrobial drug prophylaxis consisted of ticarcillin + clavulanic acid for 2 days, fluconazole 3 mg/kg/day from day 1, and aciclovir 250 mg/m ² from day 3, increased to 250 mg/m ² tds on day 5 to prevent Herpes simplex infection. On day 5 she became comatose and agitated, with choreoathetoid movements in all four limbs, random eye movements, and loss of eye contact. A brain CT scan was normal and electroencephalography showed slow waves with no evidence of seizures. The cerebrospinal fluid was normal. The trough plasma ciclosporin concentration was 87 ng/ml (below the target range of 200–250 ng/ml). The plasma aciclovir concentration was 4.5 mg/l on day 7, above the recommended target concentration (2.3 mg/l). Aciclovir was withdrawn and the neurological effects resolved.