Valaciclovir

Varicella zoster virus (VZV), the pathogen responsible for herpes zoster, belongs to the herpesvirus family and is sensitive to the antiviral drug aciclovir. However, the low oral bioavailability of aciclovir has to some extent limited its efficacy in the treatment of herpes zoster and has prompted the development of the more readily absorbed oral prodrug valaciclovir.

In a large comparative study valaciclovir, (1000mg 3 times daily for 7 days) was at least as effective as aciclovir (800mg 5 times daily for 7 days) in controlling the symptoms of acute herpes zoster. Importantly, valaciclovir alleviated zosterassociated pain and postherpetic neuralgia significantly faster than aciclovir. A 14-day regimen of valaciclovir showed no significant advantage over the 7-day regimen. A smaller trial in Japanese patients focusing primarily on the cutaneous (rash) signs of herpes zoster confirmed the similar efficacy of valaciclovir and aciclovir in the 7-day regimen. This study did not follow all patients for a formal analysis of postherpetic neuralgia. Valaciclovir and aciclovir demonstrated similar efficacy for the control of cutaneous lesions and ocular complications in patients with zoster ophthalmicus.

Preliminary results of a large controlled trial indicate that valaciclovir 1000mg 3 times daily and famciclovir (the prodrug of penciclovir) 500mg 3 times daily are of similar efficacy in speeding resolution of acute herpes zoster rash and shortening the duration of postherpetic neuralgia.

Starting treatment later than 72 hours after rash onset did not significantly reduce the beneficial effect of valaciclovir on duration of zoster-associated pain (a continuum of pain that encompasses both acute pain and postherpetic neuralgia) in a large observational study, suggesting that valaciclovir might be effective when given later than previously thought. However, valaciclovir should ideally be given as soon as possible after symptoms appear.

With the recommended regimen for the treatment of herpes zoster (1000mg 3 times daily for 7 days) valaciclovir was well tolerated, with nausea and headache being the most commonly reported adverse events. The adverse events profile of the agent was similar to that seen with aciclovir or famciclovir.

Primary infection with varicella zoster virus (VZV) causes varicella (chickenpox). When VZV reactivates from its latent state in sensory ganglia, it causes herpes zoster (shingles). Like other herpesviruses VZV is sensitive to aciclovir. The therapeutic benefit of valaciclovir in herpes zoster is based on establishing sufficiently high aciclovir concentrations in the blood for rapid penetration to sensory nerve tissue and skin for inhibition of VZV replication. After oral administration and absorption valaciclovir is hydrolysed to aciclovir and L-valine. Aciclovir is then converted to aciclovir monophosphate by VZV-encoded thymidine kinase and then to the active triphosphate form by cellular enzymes. Aciclovir triphosphate inhibits VZV (and other herpesvirus) DNA polymerase, terminating viral DNA chain elongation and preventing viral replication.

Aciclovir triphosphate inhibits replication of a range of herpesviruses including, in descending order of in vitro susceptibility, herpes simplex virus (HSV)-1, HSV-2, VZV, Epstein-Barr virus, human herpesviruses 6, 8 and 7 and cytomegalovirus. The concentration of aciclovir resulting in 50% inhibition of VZV in vitro is 0.12 to 10.8 mg/L.

VZV resistance in response to treatment with aciclovir is extremely rare in immunocompetent patients, but continued surveillance is required to determine the true incidence. The profile of VZV resistance to aciclovir after oral administration of valaciclovir is expected to be the same as after administration of aciclovir. Although still rare, aciclovir-resistant strains of VZV do occur more frequently in HIV-positive patients and transplant recipients.

In healthy volunteers and patients with herpes zoster, valaciclovir is readily absorbed from the gastrointestinal tract and undergoes rapid and extensive first-pass metabolism to yield aciclovir. In patients with herpes zoster treated with oral valaciclovir 1000mg 3 times daily the estimated bioavailability of aciclovir was approximately 4 times greater than after oral aciclovir 800mg 5 times daily in a comparator group.

In healthy adult volunteers after single 100 to 1000mg doses of valaciclovir, the peak plasma concentrations (C_max) and area under the plasma aciclovir concentration-time curve (AUC) values of aciclovir increased in a slightly less than dose-proportional manner. However, more marked dose proportionality was observed in a phase I study in healthy Japanese male volunteers who received oral valaciclovir 250 to 2000mg. In a population pharmacokinetic analysis of patients with herpes zoster treated with valaciclovir 1000mg 3 times daily the C_max was 5.73 mg/L (range 2.76 to 16.1 mg/L) and the estimated daily mean AUC for aciclovir was 88.6 mg/L · h.

Aciclovir is mainly eliminated via the renal route, but is also excreted in the faeces. In healthy volunteers who received a single dose of valaciclovir 1000mg, the mean renal clearance of aciclovir (15.3 L/h) exceeded the creatinine clearance, indicating that renal tubular secretion is actively involved in the elimination of the drug. Thus, dosage adjustment is required for patients with renal impairment. In healthy Japanese men who received valaciclovir 250 to 2000mg as a single dose the renal clearance was similar regardless of dose.

After single valaciclovir doses of 100 to 1000mg or multiple doses of 1000 to 8000 mg/day for 6 to 11 days, the plasma elimination half-life (t½) of aciclovir ranged from 2.76 to 3.3 hours; for single doses of valaciclovir 250 to 2000mg the t½ in healthy Japanese men was very similar (2.9 to 3.59 hours).

No clinically significant interactions between valaciclovir and coadministered drugs (including cimetidine, probenecid, digoxin, antacids or thiazide diuretics) have been reported. Valaciclovir may be administered with food.

The efficacy of valaciclovir for the treatment of herpes zoster has been investigated in a large number of immunocompetent patients. Trials have compared valaciclovir with placebo, aciclovir and famciclovir. A large noncomparative study has also been published.

Valaciclovir was reported in an abstract to be significantly more effective than placebo in reducing the duration of new lesion formation in patients aged between 18 and 50 years. In a pivotal study of 1141 patients ≥50 years of age with herpes zoster, valaciclovir 1000mg 3 times daily for 7 or 14 days was as effective as aciclovir 800mg 5 times daily for 7 days in speeding resolution of rash. Importantly, valaciclovir was significantly more effective than aciclovir in shortening the duration of both zoster-associated pain and postherpetic neuralgia: median duration of pain after treatment with valaciclovir for 7 or 14 days was 38 and 44 days, respectively, compared with 51 days for aciclovir, while median duration of postherpetic neuralgia was 30, 35 and 39 days for valaciclovir 7 and 14 days and aciclovir, respectively. There was no statistical difference between the beneficial effects of 7 or 14 days’ valaciclovir treatment. The 7-day regimens of valaciclovir and aciclovir have also been compared in 200 Japanese patients and the 2 treatments were similarly effective in the acute (rash) stage of the disease. Follow-up was not sufficient for statistical analysis of postherpetic neuralgia. Valaciclovir and aciclovir have also demonstrated comparable efficacy for the acute symptoms and long term complications of zoster ophthalmicus in a controlled trial in 110 patients.

Preliminary results (abstract) of a double-blind study in 597 patients aged ≥50 years indicate that valaciclovir 1000mg 3 times daily and famciclovir 500mg 3 times daily have similar efficacy in speeding resolution of zoster-associated pain, the primary end-point. Furthermore, no statistical differences were detected between the 2 drugs in rash healing rates or in postherpetic neuralgia.

Retrospective analysis of a fully published pivotal study showed that valaciclovir treatment was similarly effective whether initiated within 48 or between 48 and 72 hours of onset of rash. A large noncomparative study (n = 1897) of valaciclovir for the treatment of herpes zoster examined the influence of timing of treatment on therapeutic outcomes. Starting treatment later than 72 hours after rash onset did not significantly affect the duration of zoster-associated pain. Therefore the therapeutic window of valaciclovir may be wider than previously thought. However, valaciclovir should ideally be given as soon as possible after symptoms appear. These and other studies also examined prognostic factors associated with resolution of postherpetic neuralgia and found that patients ≥50 years of age and those experiencing more intense prodromal or acute pain, irrespective of age, were at increased risk of prolonged pain.

Quality of life (QOL) is significantly affected by herpes zoster and the influence of valaciclovir for 7 or 14 days and aciclovir for 7 days on QOL was reported as part of the large pivotal trial. QOL scores in valaciclovir-treated patients were generally improved compared with patients treated with aciclovir. The power of this trial was not sufficient for formal statistical analysis of QOL. Pharmacoeconomic issues have also been investigated and valaciclovir was found to be more cost effective than aciclovir. While this differential benefit may erode with the introduction of generic aciclovir, valaciclovir itself would still be considered cost effective in terms of the direct medical costs of managing zoster-associated pain.

Oral valaciclovir is well tolerated with an adverse event profile qualitatively and quantitatively similar to that of oral aciclovir. In immunocompetent patients treated with valaciclovir 1000mg 3 times daily for 7 days (the recommended dosage for the treatment of herpes zoster) adverse events were infrequent and generally mild, and similar to those seen in a comparator group treated with aciclovir 800mg for 5 days. The only events reported by more than 10% of patients receiving either drug were nausea and headache.

Trials comparing valaciclovir and aciclovir for the treatment of herpes zoster in Japanese patients, and for herpes zoster ophthalmicus, reported a similar range and frequency of mild gastrointestinal events and headache to that documented in the large pivotal study. No significant change from baseline in clinical chemistry or haematological parameters, and no effect on renal function was observed in either the valaciclovir- or aciclovir-treated groups in either of these comparative studies.

A similar pattern of mild events was reported in the large noncomparative trial of valaciclovir for herpes zoster carried out in a number of clinical settings, including primary care. However, the incidence of adverse events was lower than that seen in the controlled clinical studies: headache and nausea occurred, respectively, in 3 and 3.3% of patients overall.

The comparative tolerability profiles of valaciclovir and famciclovir in patients with herpes zoster were reported in an abstract and found to be similar, with headache and nausea being the most common adverse events.

The recommended dosage of valaciclovir for the treatment of herpes zoster in immunocompetent patients is 1000mg 3 times daily for 7 days. Ideally treatment should be started as soon as possible after the onset of rash, but recent data suggest that treatment initiated later than 72 hours may also be efficacious. The dosage of valaciclovir should be reduced in patients with moderate or severe renal impairment.

Valaciclovir has not been specifically studied in immunocompromised patients, although some patients with mild impairment of immunity were permitted in the Japanese studies of valaciclovir for herpes zoster. In immunocompromised individuals the exposure to aciclovir after valaciclovir (1000mg 3 times daily) is equivalent to that after intravenous aciclovir (5 mg/kg 3 times daily), therefore the use of valaciclovir in patients with mildly impaired immunity may be considered. No data are available on valaciclovir use for VZV infection in children or pregnant women.