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PubMed2006

Prevention of VZV infection in immunosuppressed patients using antiviral agents.

Antiviral agents play a key role in the prevention and treatment of varicella zoster virus (VZV) disease in immunosuppressed patients. Randomized trials show that aciclovir is effective in preventing VZV reactivation disease; however, no consensus exists on dose, duration and patient population for its use. The recent shortage of VZV-specific immunoglobulin has generated renewed interest in the use of antiviral agents as post-exposure prophylaxis. The use of antiviral agents for post-exposure prophylaxis is not supported by randomized trials, but uncontrolled experience suggests that it might be a reasonable alternative if varicella-specific immunoglobulin is not available. Current evidence on the use of antiviral agents in the prevention of reactivation disease and management of exposure to VZV is discussed.

Acyclovir↗
PubMed1995

Estimating the value of a generic quality-of-life measure.

In this paper, data from a clinical trial of a new antiviral agent for treating patients with zoster are used to answer the following question: Does the Nottingham Health Profile (NHP) add to the information obtained from the clinical measures? Three ways in which the NHP could add information are measured. First, Cox's regression analysis is used to determine whether health-related quality-of-life scores obtained at diagnosis give information about disease prognosis. Second, changes in mean NHP scores in different dimensions are computed after pain resolution to determine whether NHP scores provide more sensitive indicators of disease resolution. Third, linear regression is used to determine whether the impacts of disease on quality of life are measured adequately by the clinical parameters. These analyses show that use of the physical mobility and energy dimensions of the NHP increases understanding of disease prognosis; demonstrates the continuing impact of zoster on patients' sleep patterns and energy levels, disease symptoms not included as clinical measures, that persist after the cessation of zoster-associated pain; and gives a measure of the impact of zoster on the patient, which includes unmeasured and measured levels of severity.

Acyclovir↗
PubMed1994

Acyclovir--and beyond.

Over the past 15 years, acyclovir has become established as standard therapy for the management of herpes simplex virus infections, but there are areas where improvements might be made. Acyclovir has a relatively low oral bioavailability. As a result, valaciclovir, the L-valine ester of acyclovir, is being developed. This new drug produces enhanced plasma levels of acyclovir following oral dosing, which will not only allow more convenient dosing for the treatment of herpes simplex virus and varicella zoster virus (VZV) infections, but also mean that valaciclovir has the potential for superior clinical efficacy over acyclovir. This may broaden the potential utility of the drug to include human cytomegalovirus prophylaxis. Other new drugs in the antiherpes area include penciclovir and its pro-drug famciclovir, which have antiviral characteristics similar to acyclovir but no clinical benefit over and above that seen with acyclovir has been demonstrated. The synthesis of new specific antiherpes compounds has led to the discovery of a novel nucleoside analogue, 882C87, which has significantly greater activity against VZV than acyclovir. The compound also has a longer plasma half-life than acyclovir which may permit less frequent dosing.

Acyclovir↗
PubMedDate not supplied

Metabolic fate and pharmacokinetics of the acyclovir prodrug valaciclovir in cynomolgus monkeys.

Valaciclovir, the L-valyl ester of acyclovir (ZOVIRAX), demonstrated good oral absorption and nearly complete conversion to acyclovir in cynomolgus monkeys, indicating its suitability as an orally administered prodrug. The major urinary metabolites of [8-14C]valaciclovir, administered orally (10 and 25 mg/kg) or intravenously (10 mg/kg) to male monkeys, were acyclovir (46%-59% of urinary radioactivity), 8-hydroxyacyclovir (25%-30%), and 9-(carboxymethoxymethyl)guanine (CMMG) (11%-12%). Following oral and intravenous dosing, intact prodrug accounted for only 0.5% and 6% of urinary radioactivity, respectively. Dose-independent kinetics were observed for acyclovir derived from orally administered [8-14C]valaciclovir at the 10 and 25 mg/kg dose levels, with both AUC (24 and 60 microM.hr, respectively) and Cmax (8 and 23 microM, respectively) increasing nearly in proportion to the dose. Acyclovir was present in plasma at all sampling times (5 min to 7 hr postdose) after both oral doses, whereas the prodrug was not detected following either oral dose. The elimination of acyclovir after oral administration was monophasic, with an apparent half-life of 1.3-1.5 hr. Similar to acyclovir, both 8-hydroxyacyclovir and CMMG demonstrated dose-independent kinetics with apparent elimination half-lives of 1-1.6 hr. Intravenously administered [8-14C]valaciclovir (10 mg/kg) was rapidly converted to acyclovir, with the elimination half-life of acyclovir (0.9 hr) being 1.5-fold that of the prodrug (0.6 hr). The oral bioavailability of acyclovir derived from valaciclovir in cynomolgus monkey was 67 +/- 13%, representing a significant improvement over the limited bioavailability after acyclovir administration to primates.

Acyclovir↗
PubMedDate not supplied

Metabolic disposition of the acyclovir prodrug valaciclovir in the rat.

The prodrug valaciclovir demonstrated good oral absorption, rapid distribution and elimination, and extensive biotransformation to acyclovir in male CD rats. The mean urinary excretion of radioactivity following oral and intravenous administration of [8-14C]valaciclovir (25 mg/kg) was 65% and 95% of the dose, respectively. Acyclovir was the predominant radiolabeled urinary metabolite accounting for 57% and 65% of the dose, respectively, with valaciclovir accounting for 2% and 23% of the dose, respectively. Radioactivity from an oral dose of [8-14C]valaciclovir (10 mg/kg) was distributed to all 14 tissues examined 20 min postdose. The stomach, small intestine, kidney, liver, lymph nodes, and skin received the highest exposure to radioactivity, and the brain received the lowest exposure. Radioactivity in most tissues cleared by 24 hr postdose, and that in urine and feces accounted for essentially all of the administered dose by 48 hr postdose. Acyclovir derived from valaciclovir (10 and 25 mg/kg) exhibited dose-independent pharmacokinetics. The Cmax and AUC for acyclovir achieved with orally administered valaciclovir were 8- and 4-fold higher, respectively, than those estimated for an equivalent dose of acyclovir. The half-life of acyclovir derived from valaciclovir was approximately 1 hr, whereas that of valaciclovir was approximately 7 min. Valaciclovir was more efficiently metabolized when administered orally, indicating first-pass intestinal and/or hepatic metabolism. Rapid hydrolysis of valaciclovir in rat liver and intestinal homogenates further suggested the significance of presystemic metabolism. These studies indicate that valaciclovir is an efficient acyclovir prodrug particularly suited for oral administration.

Acyclovir↗
PubMedDate not supplied

A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group.

BACKGROUND: Valaciclovir, the 1-valyl ester of acyclovir, has provided a peroral acyclovir bioavailability 3 to 5 times that of acyclovir itself and is rapidly and completely converted to acyclovir by the liver. Accordingly, valaciclovir has the same antiviral activity as acyclovir, but the potential for enhanced clinical activity and/or less frequent administration because of its superior pharmacokinetics. METHODS: We conducted a double-blind, placebocontrolled, patient-initiated clinical trial of peroral valaciclovir, 500 or 1000 mg, or matching placebo tablets twice daily for 5 days for the acute treatment of 1 episode of recurrent herpes genitalis among 987 otherwise healthy volunteers. RESULTS: Both doses of valaciclovir were equally effective. Patients receiving the lower dose of valaciclovir experienced a median episode length of 4.0 days compared with 5.9 days for those receiving placebo treatment (hazard ratio, 1.9; 95% confidence interval [Cl], 1.6-2.3). Valaciclovir therapy increased the proportion of patients in whom the development of vesicular and ulcerative lesions was prevented in comparison with placebo treatment: 31% vs 21% (relative risk, 1.5; 95% CI, 1.1-1.9). Valaciclovir therapy accelerated the resolution of pain (hazard ratio, 1.8; 95% CI, 1.5-2.1) and the time to cessation of viral shedding (hazard ratio, 2.9; 95% CI, 2.1-3.9). Adverse reactions among the valaciclovir groups were comparable with those of the placebo group. CONCLUSIONS: Valaciclovir therapy provided a clinically significant benefit to patients that included shortening of the duration of lesions, the duration of pain or discomfort, and the duration of virus shedding. In addition, this study, to our knowledge, provides the first convincing demonstration that antiviral therapy can prevent lesion development. These results should prompt a reconsideration of the role that episodic treatment plays in the management of recurrent herpes genitalis.

Acyclovir↗
PubMed1995

Developments in the antiviral treatment of genital herpes.

There have been impressive advances made over the last decade in the management of sexually transmitted viral diseases, especially in the development of effective antiviral agents. Acyclovir, first synthesized in 1974, has proved to be an effective and safe drug for the treatment of primary and frequently recurring genital herpes, according to the various medical publications over the last 10 years. This article reviews the use of acyclovir in the treatment of genital herpes and discusses the potential problem of acyclovir resistance. It also discusses two newer antiherpes drugs, famciclovir and valaciclovir, and the preliminary results of studies on their efficacy in the treatment of genital herpes.

2-Aminopurine↗
PubMed1996

Lessons from the natural history of cytomegalovirus.

BACKGROUND: More than 90% of patients with HIV have been infected at some time with cytomegalovirus (CMV) and up to 40% of those with advanced HIV will develop CMV disease. The incidence of CMV disease is increasing but the prognosis for the patient remains poor. MONITORING FOR CMV: It is therefore important to monitor patients with low CD4+ counts in order to identify those most at risk of developing CMV disease and to treat them before the disease becomes established. Polymerase chain reaction (PCR) is probably the most effective and sensitive method of detecting CMV and a positive result is predictive for development of CMV disease; more than 80% of patients with CMV retinitis are CMV PCR-positive at the time of diagnosis. PCR can also detect the presence of CMV up to 14 months before the development of retinitis. TREATMENT OF CMV RETINITIS: In patients with detectable CMV, but no evidence of active infection, pre-emptive treatment with ganciclovir or valaciclovir has been shown to reduce the risk of developing retinitis in these high-risk patients. Such oral therapy, which is generally better tolerated than intravenous therapy and results in a better quality of life for the patient, is likely to be more effective at this stage whilst viral loads are low. CONCLUSIONS: CMV PCR can be used to prospectively monitor patients in order to identify those most at risk of developing CMV retinitis. If CMV infection is diagnosed early, while viral loads are still low, pre-emptive oral therapy can be instituted which will reduce the chances of developing retinitis in those patients most at risk.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Comparison of valaciclovir and acyclovir for the treatment of herpes zoster in immunocompetent patients over 50 years of age: a cost-consequence model.

A method was developed for modeling the costs and consequences of treating varicella zoster viral infections to clinical data generated in a pivotal phase III clinical trial of valaciclovir versus acyclovir for the treatment of acute herpes zoster in immunocompetent patients over 50 years of age. Direct medical costs and indirect costs (productivity losses) were modeled using unit costs applicable in the United States. Compared with acyclovir, valaciclovir reduced average direct medical costs per patient by 17% ($60.01) and indirect costs by an average of 25% ($46.54). Median duration of pain was reduced by 13 days for valaciclovir compared with acyclovir in the intent-to-treat population or by 19 days in patients with pain after rash healing. The cost variables described in the model (drug costs, cost of treating long-term pain, physician visits, hospitalization, treatment of severe ocular involvement, productivity losses) were tested by sensitivity analysis. Total costs associated with valaciclovir treatment remained lower than those with acyclovir over the range of the analysis.

Acute Disease↗
PubMed1996

Antiviral drugs in development for herpes zoster.

Until recently aciclovir has been the only licensed drug for the treatment of herpes zoster. A number of new drugs have emerged over the past few years which offered the potential for improved efficacy or ease of administration. With the completion of the first efficacy trials for each of these agents it has become apparent that, whilst less frequent dosing can he accomplished, it is not easy to significantly improve on the efficacy of aciclovir. Increasing age, the presence of prodromal pain and more severe pain at presentation have, however, been found to predispose to a longer duration of pain. Taking cessation of pain as the single most important parameter, at least for the older immunocompetent population as a whole, only valaciclovir has, to date, been shown to be superior to standard therapy with aciclovir. This review utilises primarily intent-to-treat data to illustrate the relative efficacy of the different therapies.

2-Aminopurine↗