A virologic pilot study of valacyclovir in infectious mononucleosis
Introduction
Primary Epstein–Barr virus (EBV) infection in adolescents and young adults causes infectious mononucleosis (Heath et al., 1972, Henke et al., 1973). The acute illness may result in loss of productivity especially among college students (Rea et al., 2001) and there are important sequelae. A causal association has been reported between infectious mononucleosis due to EBV and EBV-positive Hodgkin's lymphoma (Hjalgrim et al., 2003). Recently, symptomatic primary EBV infection has been reported to permanently scar the immune system by causing a long-term deficit in T-cell responsiveness to IL-15 (Sauce et al., 2006). EBV-seropositive individuals without a history of infectious mononucleosis did not have this immune defect. A specific treatment for infectious mononucleosis that lowers the viral load during the acute illness and/or lessens the severity of the acute illness potentially might also reduce the likelihood of its sequelae. Controlled trials of acyclovir for infectious mononucleosis, while providing some evidence of antiviral activity, have failed to conclusively demonstrate clinical efficacy (Andersson et al., 1986, Andersson et al., 1987, Pagano et al., 1983, Tynell et al., 1996, Van der Horst et al., 1991). Because this outcome might reflect the design of the clinical trials, the drug and the dosage studied, or the methods used to quantitate EBV, we decided to reevaluate antiviral therapy of infectious mononucleosis. We performed a virologic pilot study with valacyclovir, a prodrug of acyclovir that has three to five times better oral bioavailability (Soul-Lawton et al., 1995). A quantitative EBV real-time PCR (qEBV) assay was used to measure EBV in oral and blood compartments. The clinical course was evaluated with a severity of illness score (Balfour et al., 2005) and an analysis of the proportion of subjects reporting symptoms at each study visit.
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Clinical trial design
This randomized, controlled clinical trial was conducted under FDA investigator-sponsored IND 68,519 and is registered at http://www.clinicaltrials.gov (registration number, NCT00274404). Participants were assigned to receive valacyclovir (1 g every 8 h for 14 days) or no antiviral drug (control subjects; no placebo was administered) according to a computer-generated random code. Personnel performing laboratory tests, data entry, and data analysis were blinded to the study group assignment until
Characteristics of the study participants
Between February 2004 and September 2005, we screened 34 subjects, enrolled 28 of them, and analyzed data from the 20 subjects who had laboratory-confirmed primary EBV infection and completed at least the first 3 weeks of their scheduled visits. Data from eight subjects who enrolled were not included in the final analysis. Seven of them were excluded because they did not have primary EBV infections. Five of these seven had past infections and two had no confirmation of EBV infection. One
Discussion
Valacyclovir significantly decreased the amount of EBV in the oral washes of university students who had laboratory-documented primary EBV infections during the treatment period. The median EBV viral loads in both the oral wash-derived cell pellet and supernatant samples were below the limit of detection in the valacyclovir subjects for the majority of the 14-day treatment period. There was a trend toward a clinical benefit by both the analysis of the severity of illness scores and the
Acknowledgments
We are indebted to the University of Minnesota students who participated in the clinical trial, the staff of the Boynton Health Service who referred them, and the personnel of the Clinical Virology Laboratory of the University of Minnesota, Fairview for the performance of the EBV antibody tests. This study was approved by the University of Minnesota Institutional Review Board and the Boynton Health Service Research Committee. Informed consent was obtained from each subject prior to enrollment.
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