Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose Acyclovir / Aciclovir and ganciclovir.

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3-80.7) months. herpes simplex virus antibody positive (HSV+) patients received Acyclovir / Aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise Acyclovir / Aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, Acyclovir / Aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6-19%) at 12 months, 32% (22-42%) at 24 months and 38% (27-50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving Acyclovir / Aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20-46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. We conclude that 3-6 months of low-dose Acyclovir / Aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD.

Valacyclovir ( Valtrex ): a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2.

Valacyclovir ( Valtrex ) is a prodrug of the antiviral agent Acyclovir / Aciclovir and it does not contain a peptide bond in its structure. We studied the interaction of Valacyclovir ( Valtrex ) with the peptide transporters in the human intestinal cell line Caco-2 and the rat kidney proximal tubular cell line SKPT which differentially express peptide transporters PEPT1 and PEPT2. The results of the studies done with these cell lines were confirmed with the cloned peptide transporters human PEPT1 and rat PEPT2, expressed heterologously in HeLa cells. The activity of the peptide transporters was assessed by measuring the uptake of radiolabeled glycylsarcosine in the presence of a H+ gradient. Valacyclovir ( Valtrex ) inhibited the uptake of glycylsarcosine with an inhibition constant (Ki) of 0.49 +/- 0.04 mM in Caco-2 cells and 0.17 +/- 0.01 mM in SKPT cells. In both cell types, the inhibition was competitive. Acyclovir / Aciclovir, in contrast to Valacyclovir ( Valtrex ), did not interact with the peptide transporters. Similar results were obtained with heterologously expressed human PEPT1 and rat PEPT2. Valacyclovir ( Valtrex ) inhibited the hPEPT1-mediated glycylsarcosine transport competitively with a Ki value of 0.74 +/- 0.14 mM. The rPEPT2-mediated transport of glycylsarcosine was also inhibited by Valacyclovir ( Valtrex ) competitively and the Ki value for the process was 0.39 +/- 0.03 mM. Acyclovir / Aciclovir did not interact with either of these cloned peptide transporters. We conclude that Valacyclovir ( Valtrex ) is a substrate for the peptide transporters PEPT1 and PEPT2 and that a peptide bond is not a prerequisite for recognition as a substrate by the peptide transporters.

Recent developments in Herpes virus therapy.

The antiherpes drugs, Acyclovir / Aciclovir and ganciclovir, are considered the standard treatments and prophylactic agents for infections caused by herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV). Until a decade ago, the impact of Acyclovir / Aciclovir on the control of severe and life-threatening Herpes virus infections was unprecedented. During the past few years, we have witnessed approval of new therapeutic drugs for infections caused by HSV and VZV (i.e. Penciclovir ( Denavir ) and the oral prodrugs, valAcyclovir / Aciclovir and Famciclovir ( Famvir )), CMV (i.e. ganciclovir, cidofovir and fomivirsen) or HSV, VZV and CMV (i.e. foscarnet). A few agents, such as brivudin and benzimidavir, are in ongoing clinical development; others have been suspended because of safety concerns. New antiherpes agents are needed to face clinical issues such as drug resistance, increased use of antiherpes prophylaxis in transplantation and safety concerns in small children or pregnant women.

Persistence and transition of Epstein-Barr virus genotypes in the pathogenesis of oral hairy leukoplakia.

This prospective study examined the persistence and transition of Epstein-Barr virus (EBV) in human immunodeficiency virus (HIV)-seropositive subjects with and without oral hairy leukoplakia, a replicative EBV-associated epithelial disease. The intrahost molecular epidemiology of EBV infection was characterized in subjects treated with Valacyclovir ( Valtrex ) to suppress EBV replication. Tongue epithelial tissues of HIV-seropositive subjects were found to support not only EBV replication but also persistent, nonproductive EBV infection. EBV appeared to enter the tongue from the blood reservoir of infection and, possibly, from exogenous sources as well. EBV transition from the blood to the tongue appeared to occur even during Valacyclovir ( Valtrex )-mediated suppression of EBV replication, suggesting EBV entry into tongue epithelial tissue as a cell-associated latent infection. In conclusion, these results describe the persistence and transition of EBV as a dynamic interaction between the blood and epithelial reservoirs of EBV infection and suggest a role for entry, persistence, and reactivation of oral epithelial EBV in the pathogenesis of oral hairy leukoplakia.