Journal of Clinical Virology 43 (2008) 212–215 Contents lists available at ScienceDirect Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv Foscarnet salvage therapy efficacy is associated with the presence of thymidine-associated mutations (TAMs) in HIV-infected patients  Charlotte Charpentier a,b , Didier Laureillard c , Mustapha Sodqi c , Ali Si-Mohamed a , Marina Karmochkine c , Laurent Bélec a,b , Laurence Weiss b,c , Christophe Piketty b,c,∗ a Laboratoire de Virologie, AP-HP, Hôpital Européen Georges Pompidou, Paris, France b Université Paris-Descartes, Faculté de Médecine, Paris, France c Service d’Immunologie Clinique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France article info Article history: Received 22 September 2007 Received in revised form 1 July 2008 Accepted 1 July 2008 Keywords: HIV Foscarnet Salvage therapy Thymidine-associated mutations abstract Background: Salvage therapy based on foscarnet plus a thymidine analog is effective in patients with advanced-stage HIV disease and viruses harbouring multiple drug-resistance mutations. Objective: To identify viral genetic determinants associated with the virological efficacy of foscarnet salvage therapy. Study design: Thirteen patients received foscarnet at a fixed dose of 80mg/kg twice daily for 14 days, in combination with zidovudine or stavudine. Results: The baseline median HIV viral load and CD4 cell count were 5.10 log 10 copies/ml and 23 cells/mm 3 , respectively. Following foscarnet therapy, viral load fell by a median of 1.84log 10 copies/ml (range: -0.29 to -2.82), and by at least 1 log 10 copies/ml in 11 patients, all of whom harboured viruses with at least three thymidine-associated mutations (TAMs). The two patients with smaller declines in viral load (<0.50 log 10 copies/ml) harboured viruses with only one or zero TAMs. Conclusions: These findings corroborate, in vivo, the impact of TAMs on HIV susceptibility to foscarnet. The virological response to foscarnet salvage therapy in multiclass-experienced patients may thus differ according to the number of TAMs. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Foscarnet is a pyrophosphate (PP i ) analog with activity on various viral DNA polymerases in vitro, including HIV reverse tran- scriptase (RT). Foscarnet is mainly used to treat cytomegalovirus (CMV) infection. Ten years ago, HIV plasma viral load was observed to fall during foscarnet treatment of CMV retinitis. 1–3 However, the advent of highly active antiretroviral therapy (HAART), together with the need for intravenous administration and frequent nephro- toxicity, restricted the evaluation of foscarnet in the treatment of HIV infection. Foscarnet has been used as salvage therapy for patients with late-stage HIV infection and few other therapeutic options. Two studies involved patients with low CD4 cell counts, virologi-  Presented in part: XVI International HIV Drug Resistance Workshop, Los Barba- dos, West Indies, June 2007; Abstract 116. ∗ Corresponding author at: Département d’Immunologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France. Tel.: +33 1 56 09 27 01; fax: +33 1 56 09 28 59. E-mail address: christophe.piketty@egp.aphp.fr (C. Piketty). cal failure, and multidrug-resistant (MDR) viruses. 4,5 Mathiesen et al. reported that HIV plasma viral load fell by a median of 1.80 log 10 copies/ml (range: -1.20 to -3.20) after 2 weeks (W2) of foscarnet therapy in seven patients. 4 More recently, Canestri et al. obtained similar results in 11 patients, with a median decrease of 1.99 log 10 copies/ml (range: -0.50 to -2.49) at week 2 of foscarnet- zidovudine (AZT) combination therapy. 5 Being a PP i analog, foscarnet acts as a substrate for phosphoroly- sis and is able to block the excision of chain-terminating nucleotides catalysed by HIV RT. 6 Excision of chain-terminating nucleotides is the main mechanism of resistance to thymidine analogs (AZT and d4T). TAMs increase the capacity of RT to remove thymidine analogs from growing DNA chains. A negative correlation has been observed between the degree of HIV resistance to AZT and to foscarnet. 7,8 TAMs confer resistance to AZT but also hypersusceptibility to fos- carnet in vitro. In addition, mutations associated with foscarnet resistance can reduce or even overcome phenotypic resistance to AZT among viruses harbouring TAMs. 7,8 Here we evaluated foscarnet, in combination with a thymi- dine analog, as salvage therapy in 13 HIV-infected patients with severe immunodeficiency, multiple virological failure, and MDR viruses. 1386-6532/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2008.07.001