Valaciclovir (
Valtrex, Zelitrex), the
L-valine ester of
aciclovir, increases
aciclovir bioavailability by 3- to 5-fold over that achievable with oral
aciclovir. It addresses many unmet needs of currently available anti-herpesvirus
therapies.
Valaciclovir extends the efficacy of
aciclovir in the treatment of
herpes zoster and genital HSV
infections, using less frequent dose regimens but retaining the highly acceptable safety profile established for
aciclovir. The potential for
valaciclovir in CMV prophylaxis has now been proven, and further refining to identify the optimal dose regimen is ongoing. After
oral administration,
valaciclovir is rapidly absorbed and extensively converted to
aciclovir and
L-valine, the
essential amino acid. The mode of action and spectrum of
antiviral activity of
valaciclovir are thus identical to
aciclovir. The bioavailability of
aciclovir after
valaciclovir, characterised from studies in healthy adult volunteers, is similar in a wide range of patient populations, including the elderly, those with advanced HIV disease, patients with impaired liver or renal function, or undergoing
bone marrow transplantation. No clinically significant drug interactions with
valaciclovir have so far been identified. Dosage reductions in clinical use of
valaciclovir are only necessary when renal function is severely impaired. In controlled clinical trials in
herpes zoster,
valaciclovir (1000 mg three times daily) is superior to
aciclovir in speeding the resolution of
zoster-associated
pain and post-herpetic
neuralgia. It is as effective as
aciclovir in hastening
rash healing. In patients with ophthalmic
zoster, no differences were evident between
valaciclovir and
aciclovir treatment on
zoster-associated
pain or the occurrence of ocular complications. The safety profiles of
valaciclovir,
aciclovir and placebo were not different in this study programme. In a series of controlled, randomised trials of
valaciclovir,
aciclovir and placebo for the acute treatment of genital HSV
infections in approximately 3000 patients, twice daily
valaciclovir was proven as effective as the standard 5 times daily
aciclovir regimen in resolving the clinical signs and symptoms of lesional disease. Early patient-initiated
valaciclovir therapy (500 mg twice daily) of recurrent
genital herpes episodes was shown significantly to increase the chance of prevention of vesicular or ulcerative lesions, a valuable clinical advantage not prospectively proven for
aciclovir. When used for periods of up to one year,
valaciclovir (500 mg once daily) effectively suppresses
genital herpes recurrences. Long-term studies of
valaciclovir for HSV suppression, evaluating doses of up to 1000 mg daily in approximately 3000 patients, about 25% of whom were HIV seropositive (CD+ > 100 cells/microl), revealed a highly acceptable clinical tolerability profile for
valaciclovir that did not differ from
aciclovir or placebo. There were no cases resembling
thrombotic microangiopathy in these long-term studies. The
aciclovir safety heritage and pharmacokinetic rationale for the development of
valaciclovir have been realised through the clinical research programmes in the
zoster and HSV indications. Further studies in these and related areas, including CMV prophylaxis, are in progress and aim to expand further the clinical potential of
valaciclovir in the future.