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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Antimicrob+Agents+Chemother
2013 ; 57
(12
): 5820-9
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gab.com Text
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Rapid viral expansion and short drug half-life explain the incomplete
effectiveness of current herpes simplex virus 2-directed antiviral agents
#MMPMID24018260
Schiffer JT
; Swan DA
; Corey L
; Wald A
Antimicrob Agents Chemother
2013[Dec]; 57
(12
): 5820-9
PMID24018260
show ga
The nucleoside analogues acyclovir (ACV) and famciclovir (FCV) reduce the
frequency and severity of herpes simplex virus 2 (HSV-2) genital shedding, yet
despite their high potency in vitro and a lack of induced drug resistance,
frequent episodes of breakthrough mucosal shedding occur. We tested a published
stochastic, spatial mathematical model of HSV-2 replication and spread, in
concert with pharmacokinetic and pharmacodynamic equations, against virologic
data from clinical trials of twice-daily acyclovir and famciclovir suppression.
The model reproduced the key features of clinical trial data, including genital
shedding episode rate, expansion and decay dynamics, and heterogeneous peak viral
production and duration. In simulations, these agents shortened episode duration
by limiting the extent of viral production by 1 to 2 log units and limiting the
formation of secondary ulcers by ?50%. However, drug concentrations were
noninhibitory during 42% of the dosing cycle. Even if drug concentrations were
high at episode initiation, prolonged episodes often ensued due to drug decay
over ensuing hours and subsequent rebound of rapidly replicating HSV-2. The local
CD8(+) T-cell density was more predictive of episode viral production (R(2) =
0.42) and duration (R(2) = 0.21) than the drug concentration at episode onset
(R(2) = 0.14 and 0.05, respectively), though the model projected that an agent
with an equivalent potency but a two times longer half-life would decrease
shedding by 80% compared to that of standard twice-daily regimens. Therefore,
long half-life is a key characteristic of any agent that might fully suppress
HSV-2 reactivations.