Research Article: Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection

Date Published: April 13, 2017

Publisher: Public Library of Science

Author(s): Jessica Rose, Vincent C. Emery, Deepali Kumar, Anders Asberg, Anders Hartmann, Alan G. Jardine, Angelo A. Bignamini, Atul Humar, Avidan U. Neumann, Donald M. Coen.

http://doi.org/10.1371/journal.ppat.1006299

Abstract

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues.

Partial Text

Human cytomegalovirus (CMV), a member of the beta herpesvirus sub-family, has co-evolved with humans over many millennia and usually does not cause disease in the immunocompetent host [1,2]. However, in a variety of immune deficient/immature hosts including the neonate, organ transplant recipients, patients with common variable immune deficiency (CVID) and Human Immunodeficiency Virus (HIV)-infected patients, the virus can cause life-threatening pathologies [3,4]. Thus, CMV has a significant economic impact on general healthcare costs, especially in the transplant setting [5]. Despite recent encouraging results, there is no licensed vaccine against CMV[6–8]. Consequently, antiviral chemotherapy using ganciclovir (GCV) or its valine ester valganciclovir (VGCV) is currently the major clinical management tool. The drug can be given prophylactically, pre-emptively or for therapy of overt CMV syndrome and disease [9] although questions related to dosing and duration of treatment remain open [10,11].

Understanding CMV replication in the human host and identifying predictors for the response to therapy remains important for the clinical management of this infection in the immunocompromised host. Until now, our understanding of CMV kinetics following therapy has been limited to deploying basic models of viral dynamics. The availability of datasets from large clinical trials of antiviral medication with frequent (in particular measurement as early as day 3 of treatment) and precise (using an assay with less than 0.15 log variability) with viral load measurements is invaluable to determine viral kinetics during therapy. Using data from a clinical trial [29] comparing intravenous GCV with a valine ester pro-drug of GCV [3], we were able to both identify and validate, in 2 separate groups of patients, four distinct kinetic patterns of CMV decline during the first 21 days of therapy. While two profile patterns had been previously observed (Biphasic and Delay) [25,27,32], two new profile patterns (Hump and Rebound) were observed. The Hump (HM) profile, characterized by a rapid decline in viral load followed by a transient increase and a subsequent second phase decline, occurred in a significant proportion of the patients and was unexpected. Re-evaluation of other CMV viral load decline data from previous studies [25] indeed clearly indicates the presence of a Hump profile in some patients.

 

Source:

http://doi.org/10.1371/journal.ppat.1006299

 

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