Title Participants "The efficacy and safety of zidovudine alone or as cotherapy with acyclovir for the treatment of patients with AIDS and AIDS-related complex; a double-blind, randomized trial" "DA Cooper, PO Pehrson, C Pedersen, M Moroni, E Oksenhendler, W Rozenbaum, N Clumeck, V Faber, W Stille, B Hirschel, C Farthing, R Doherty, JM Yeo, Group European-Australian Collaborative" "The efficacy and safety of zidovudine with or without acyclovir in the treatment of patients with AIDS-related complex" "DA Cooper, C Pedersen, F Aiuti, JL Vilde, M Ruhnke, O Pehrson, N Clumeck, C Farthing, L Rüedi, RR Doherty, PA Cload, Group The European-Australian Collaborative" "Topical use of 5% acyclovir cream for the treatment of occult and verrucous equine sarcoids : a double-blinded placebo-controlled study" "Maarten Haspeslagh, Mireia Jordana Garcia, Lieven Vlaminck" "Topical distribution of acyclovir in normal equine skin and equine sarcoids : an in vitro study" "Maarten Haspeslagh, Lien Taevernier, An Maes, Lieven Vlaminck, Bart De Spiegeleer" "Determination of acyclovir in horse plasma and body fluids by high-performance liquid chromatography combined with fluorescence detection and heated electrospray ionization tandem mass spectrometry" "An Maes, Barbara Garré, Noël Desmet, K van der Meulen, Hans Nauwynck, Patrick De Backer" "Pharmacokinetics and clinical efficacy of acyclovir in the treatment of equine herpes virus type 1 infections" "Barbara Garré" "Is acyclovir effective among critically ill patients with herpes simplex in the respiratory tract?" "Stephanie Traen, Niels Bochanen, Margareta Ieven, Tom Schepens, Peggy Bruynseels, Walter Verbrugghe, Philippe Jorens" "Background and objective: The relevance of the detection of herpes simplex virus type 1 (HSV-1) in the respiratory tract of patients in the intensive care unit (ICU) is unclear. Therefore, it is uncertain whether treatment with an antiviral agent could be beneficial for these patients. Study design: We retrospectively reviewed the records of ICU patients with a positive HSV-1 culture in the respiratory tract or bronchoalveolar lavage (BAL) fluid. We evaluated whether acyclovir treatment (n=106) could have a beneficial effect on mortality as compared with the standard treatment (n=106). Results: Acyclovir treatment was positively linked to in-hospital and ICU-mortality reduction. This favourable influence remained present after correcting for possible confounders and using propensityadjusted and propensity-matched cohorts: with an odds ratio in the treated group of 3.19 (95% CI 1.79-5.69, p = 0.001) for ICU survival and of 3.55 (95% CI 2.16-5.85, p< 0.001) for in-hospital survival. The subgroup with HSV-1 detected in the BAL-fluid is the sole contributor to this difference. In the BAL-fluid detected group, 48% (n=10) of non-treated patients died in the ICU, versus 21% (n= 6) in the acyclovir-treated group (p =0.033), occurring despite an even longer duration of ventilation or ICU stay. Conclusions: These data highlight the hypothesis that it might be worthwhile to consider treatment of HSV-1 in ICU patients depending on the type of respiratory sample in which the virus is detected. These results warrant a prospective trial to prove causality. (C) 2014 Elsevier B.V. All rights reserved." "Acyclovir resistance in herpes simplex viruses: Prevalence and therapeutic alternatives" "Hanna Schalkwijk, Robert Snoeck, Graciela Andrei" "Herpes simplex viruses (HSV), the causative agents of recurrent orofacial and anogenital infections, can cause significant morbidity and mortality in both immunocompetent and immunocompromised individuals. In immunocompromised patients, HSV tends to be more persistent with chance of dissemination. The nucleoside analogue acyclovir has drastically improved the management of HSV infections although acyclovir resistant strains have been reported in the clinic. We performed a systematic search to summarize the prevalence data reported in both the immunocompetent and immunocompromised populations. Defining the global prevalence of acyclovir resistance in HSV infections is hampered by the high variability in methodology, patient selection, study design, and treatment history among the studies. Acyclovir resistant HSV is infrequent in the immunocompetent population (generally below 1%), irrespective of treatment history. Exceptions are infections at immune-privileged sites such as the cornea, where frequent recurrences and extensive acyclovir therapy favor the emergence of acyclovir resistance. Higher frequencies of acyclovir resistant HSV infections are reported among immunocompromised individuals, with the highest prevalence seen among hematopoietic stem cell transplant recipients. All antivirals approved for the treatment of HSV infections have the same target, i.e. the viral DNA polymerase, and cross-resistance to different antivirals has been described, complicating therapy of acyclovir resistant strains. In this review we will discuss acyclovir mode of action, mechanisms of resistance, prevalence of resistance, and alternative antiviral treatments for acyclovir resistant HSV infections." "A new class of dual-targeted antivirals: monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2" "Dominique Schols, Jan Balzarini" "BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) are responsible for 2 intersecting epidemics in which the disease caused by 1 virus facilitates the transmission of and pathogenesis by the other. Therefore, suppression of one virus infection will affect the other. Acyclovir, a common antiherpetic drug, was shown to directly suppress both viruses in coinfected tissues. However, both antiviral activities of acyclovir are dependent on phosphorylation by the nucleoside kinase activity of coinfecting human herpesviruses. METHODS: We developed acyclovir ProTides, monophosphorylated acyclovir with the phosphate group masked by lipophilic groups to allow efficient cellular uptake, and investigated their antiviral potential in cell lines and in human tissues ex vivo. RESULTS: Acyclovir ProTides suppressed both HIV-1 and HSV-2 at median effective concentrations in the submicromolar range in ex vivo lymphoid and cervicovaginal human tissues and at 3-12 micromol/L in CD4(+) T cells. Acyclovir ProTides retained activity against acyclovir-resistant HSV-2. CONCLUSIONS: Acyclovir ProTides represent a new class of antivirals that suppress both HIV-1 and HSV-2 by directly and independently blocking the key replicative enzymes of both viruses. Further optimization of such compounds may lead to double-targeted antivirals that can prevent viral transmission and treat the 2 synergistic diseases caused by HIV-1 and HSV-2. To our knowledge, the acyclovir ProTides described here represent the first example of acyclic nucleoside monophosphate prodrugs being active against HIV-1." "The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir" "Patrick Augustijns" "Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed."