The combination of valacyclovir with an anti-TNF alpha antibody increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis

The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an antitumor necrosis factor alpha (TNF-alpha) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85 x 10(4) plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 mu g/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P = 0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P < 0.01) or combined with ETA (P < 0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-alpha, inhibitor, to improve prognosis of HSE. (C) 2013 Elsevier B.V. All rights reserved.