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Foscarnet used in salvage therapy of HIV-1 patients harbouring multiple nucleotide excision mutations

2004; Lippincott Williams & Wilkins; Volume: 18; Issue: 7 Linguagem: Inglês

10.1097/00002030-200404300-00020

1473-5571

Sofie Mathiesen, Birgit Thorup Røge, Nina Weis, Jens Lundgren, Niels Obel, Jan Gerstoft,

Cytomegalovirus and herpesvirus research

We used foscarnet as induction therapy or as maintenance therapy in different dosing regimens in seven severely immunocompromised multidrug-resistant HIV-1 patients. During induction the median decrease in viral load was 1.8 log and increases in CD4 cell counts ranging from zero to 136 cells/mm3were observed during maintenance therapy, suggesting that foscarnet could be an option in salvage therapy in patients with no treatment options left. Foscarnet is a pyrophosphate analogue and inhibits several viral polymerases, including HIV-1 reverse transcriptase, presumably by binding close to the binding site of pyrophosphate. Foscarnet has been used in the treatment of cytomegalovirus retinitis in AIDS patients, and several early studies reported a variable inhibitory effect on plasma HIV-1 RNA levels [1–3]. However, the use of foscarnet has been limited because of the need for intravenous administration, nephrotoxicity, and the introduction of new, strong and well-tolerated oral antiretroviral drugs. In-vitro assays have proved that the presence of nucleotide excision mutations (NEM) confer phenotypic hypersusceptibility to foscarnet, and that foscarnet resistance mutations reverse pre-existing zidovudine resistance through a reduction of the pyrophosphorolytic excision of the incorporated nucleoside analogue [4,5]. We have thus used foscarnet as salvage therapy in seven severely immunocompromised and multidrug-resistant HIV-1-infected patients harbouring three or more NEM, and present the short-term outcome. The treatment was initiated as sequential inductions, and in some cases continued as maintenance therapy at the treating physician's initiative. All data are presented as median values followed by ranges in brackets. The patients were initially foscarnet naive although heavily pre-treated, having received antiretroviral therapy for 9 years (7–11). They had been exposed to 14 (12–14) different antiretroviral drugs. Genotyping at baseline revealed the presence of multidrug-resistant viruses harbouring seven (five to nine) nucleoside reverse transcriptase inhibitor (NRTI) mutations including three or more NEM, nine (six to 12) protease inhibitor mutations, and two (one to three) non-NRTI mutations. The mutations were classified according to the table from the International AIDS Society, USA, March 2003. Before foscarnet treatment the HIV-1-RNA level and CD4 cell count were 165 500 copies/ml (93 000–1 440 000) and 17 cells/mm3 (9–56), respectively, during ongoing highly active antiretroviral therapy to which all patients were considered to be strictly adherent. During treatment with foscarnet, all patients continued their backbone highly active antiretroviral therapy, with minor adjustments: tenofovir was suspended in four patients in order to avoid a potential additive nephrotoxic effect, and patient 6 had didanosine added. Enfurvitide (T-20) was available in an expanded access programme and was prescribed in four of the patients, but was initiated after foscarnet induction was completed. The reported effect on viral load and CD4 cell counts in this paper is assessed before the administration of enfurvitide. Six patients received foscarnet as induction therapy, defined as 60 mg/kg three times a day. The daily fluid intake was required to be greater than 3 l. The patients received foscarnet for 14 days (5–17). The objective was an induction period of 14 days, but the period had to be modified according to the patients' requests and the availability of drug. At the end of foscarnet induction the decrease in viral load and increase in CD4 cell counts were 1.8 logs (1.2–3.2) and 8 cells/mm3 (−19–56), respectively. In patients having sequential inductions, the decline in viral load was observed repetitively (Fig. 1). A rapid virological rebound was observed when foscarnet was suspended.Fig. 1.: Diagrams showing HIV-1 RNA and CD4 cell count. Black bars indicate foscarnet induction therapy, grey bars indicate maintenance therapy with the applied dose noted in the individual diagram. Please note the different scales for the CD4 cell count. Resistance-related reverse transcriptase mutations at baseline are listed for the individual patient. In patient 5, 210W and 184V were not present at the first induction.Four patients initiated foscarnet as maintenance therapy, three as a rollover from induction. The dosing regimens varied from 90 mg/kg a day, 60 mg/kg twice a day and 90 mg/kg twice a day (Fig. 1). Up to now patients have received maintenance therapy for 1–8 weeks. The latest available measurements during maintenance therapy show a decrease in viral load of 0.6 logs (0.3–1.0) and an increase in CD4 cell counts of 47 cells/mm3 (0–136) from baseline. The extent of viral suppression observed during induction was not fully sustained, and all patients experienced a partial virological rebound when the dose was reduced as maintenance therapy was initiated (Fig. 1). Three out of four patients experienced an increase in CD4 cell counts (Fig. 1). Patient 4 also received anti-tumour chemotherapy on the indication of Kaposi's sarcoma and had no immunological response during foscarnet treatment. Treatment was interrupted in patients 4 and 6 because of renal impairment or infection originating from the intravenous device. A marked decline in HIV-1-RNA levels ranging from 1.0 to 3.2 logs was observed during induction therapy with foscarnet. Maintenance therapy was associated with increases in CD4 cell counts despite the fact that the initial decrease in viral load during induction therapy was not fully sustained. The blunted virological response during maintenance therapy could be caused by the reduced doses of foscarnet, the prolonged dosing interval or the development of resistance. The rapid virological rebound when foscarnet was stopped further indicates that the decline in viral load can be ascribed to the effect of foscarnet. Delineation of the enzymatic background of zidovudine resistance revealed that accelerated removal of the incorporated nucleoside analogue mediated by pyrophosphate or adenosine triphosphate formed the basis of resistance in viral strains harbouring NEM, a finding later extended to other nucleoside analogues [6]. Whether the accumulated number of NEM in our patients had an impact on the observed effect of foscarnet remains speculative. However, in theory these mutations induce hypersusceptibility to foscarnet and inhibit the accumulation of foscarnet resistance mutations [5–7]. A hypothetical explanation of the pronounced response could be that foscarnet directly interferes with the pyrophosphorolytic activity and to some extent restores susceptibility to the NRTIs. Two of our patients had to stop treatment as a result of renal impairment and infection originating from the intravenous device. Foscarnet toxicity and the risk of severe infections related to intravenous administration represent a major limitation in clinical practice. Therefore, regardless of the promising antiretroviral properties, treatment with foscarnet should be instituted with great caution and restricted to patients with severely deteriorated immunology and no other treatment options left. The objective of therapy should be to identify tolerable maintenance doses that provide a reasonable improvement in the CD4 cell count. In order to define the clinical application of foscarnet as salvage therapy, optimal dosing regimens, the optimization of toxicity management and an improved understanding of the mode of action are required. We have presented the short-term outcome in seven consecutive case histories, and whether the results are reproducible will have to be determined in controlled trials. Comparative trials with other treatment modalities are thus warranted, and the most favourable combinations with other antiretroviral drugs remain to be elucidated.