Antiviral activity of foscarnet in salvage therapy
2 June 2004. Related: Antiretrovirals.
Graham McKerrow, HIV i-Base
Another small study has reported short-term antiviral activity from foscarnet use in salvage therapy for seven patients with multi-drug resistant HIV-1.
Sophie Mathiesen and colleagues in Denmark used foscarnet as induction therapy or as maintenance therapy in different dosing regimens for seven severely immunocompromised patients harbouring three or more nucleotide excision mutations (NEM). During induction the median decrease in viral load was 1.8 log and increases in CD4 cell counts ranged from 0 – 136 cells/mm3.
The patients were foscarnet naïve although heavily pre-treated having received ARVs for a median 9 years (range 7-11), and had been exposed to 14 (12-14) different ARVs. They had multidrug-resistant virus harbouring 7 (5-9) NRTI mutations including 3 or more NEM, 9 (6-12) PI mutations and 2 (1-3) non-NRTI mutations.
Before treatment with foscarnet, the HIV RNA level was 165,000 copies/ml (93,000-1,440,000) and the CD4 count was 17 cells/mm3 (9-56). All patients continued their HAART regimens, with minor adjustments, during foscarnet treatment. Six patients received foscarnet as induction therapy (60 mg/kg three times a day) for 14 days (5-17).
At the end of foscarnet induction, viral load had decreased 1.8 logs (1.2-3.2) and CD4 cells had increased 8 cells/mm3 (-19-56). Four patients initiated foscarnet as maintenance therapy, three as a rollover from induction, with various dosing regimes. The patients had received maintenance therapy for 1-8 weeks. Treatment was interrupted in 2 patients because of renal impairment or infection originating from the intravenous device.
The authors write: “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.”
The authors advise: “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.”The authors advise: “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.”
Comment
Foscarnet was assessed for antiretroviral activity in vivo in a number of pilot studies or as part of CMV-therapy. There was never a profound effect reported in patients on monotherapy or as part of a multiple drug regimen in salvage therapy.
Foscarnet has to be given IV two to three times a day in the induction phase of CMV treatment and also requires careful preadministration of probenecid to limit renal toxicity. Its optimal antiretroviral use is unknown.
The development of an orally available prodrug of foscarnet was stopped by AstraZeneca the manufacturer after CMV-retinitis became a rare disease.
Although the potential antiviral activity indicated by this study could be useful in a few patients, the significant toxicity indicates that they are likely to those with CD4 counts <50 who also require treatment for active CMV.
Reference:
Mathiesen S, Roge B, Weis N et al. Foscarnet used in salvage therapy of HIV-1 patients harbouring multiple nucleotide excision mutations. AIDS: Volume 18(7) 30 April 2004 pp 1076-1078