, Volume 48, Issue 2, pp 199-226
Date: 11 Dec 2012

Foscarnet

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

Synopsis

The DNA polymerase of human herpes viruses, including cytomegalovirus (CMV), and the reverse transcriptase of human immunodeficiency virus (HIV) are selectively inhibited in vitro by the pyrophosphate analogue foscarnet. Inhibition is reversible on withdrawal of foscarnet and additive or synergistic effects have been demonstrated in vitro with other antiviral drugs, including ganciclovir and zidovudine. Foscarnet appears to have negligible effects on host enzymes and cells.

Complete or partial clinical resolution of ocular symptoms is obtained in more than 89% of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis during foscarnet induction therapy, but relapse occurs soon after ceasing treatment. Maintenance treatment given daily can extend the period of remission considerably. Foscarnet and ganciclovir monotherapy had similar efficacy in the treatment of CMV retinitis in patients with AIDS in several studies, and have been used concomitantly in immunocompromised patients with recalcitrant CMV infections. In 1 trial, patients receiving foscarnet survived for significantly longer than those receiving ganciclovir.

Foscarnet has been used successfully in the treatment of limited numbers of immunocompromised patients with CMV-associated gastrointestinal (improvement in over 67% of patients) and other infections. Aciclovir-resistant herpes simplex infections in immunocompromised patients have also been treated successfully with foscarnet.

Almost 90% of a foscarnet dose is excreted in the urine. Reversible nephrotoxicity is common during foscarnet therapy, but may be reduced by dosage adjustment and adequate hydration. Anaemia, nausea and vomiting, disturbances in electrolyte levels and genital ulceration have also been associated with administration of the drug. The different tolerability profiles of foscarnet and zidovudine facilitate the use of these agents in combination in patients with AIDS and CMV infection; whereas ganciclovir, like zidovudine, is associated with dose-limiting haematological toxicity. The apparent survival benefits seen in these patients when receiving foscarnet and zidovudine (possibly linked to synergy between zidovudine and foscarnet and/or the inherent anti-HIV activity of foscarnet), appear to offer potentially important advantages for foscarnet over ganciclovir in the treatment of selected patients with AIDS and CMV infections.

Antiviral Activity

The pyrophosphate analogue foscarnet prevents replication of human herpes viruses, including cytomegalovirus (CMV), and also human immunodeficiency virus (HIV). Foscarnet concentrations of 0.1 to 0.5 umol/L inhibit CMV DNA polymerase and HIV reverse transcriptase activity by 50%. In contrast, the effects of foscarnet on host enzymes and cells appear to be negligible.

Inhibition of viral replication is reversible, with viral cytopathic effects restored on withdrawal of foscarnet. Foscarnet concentrations of about 6 to 55 (imol/L caused 50% inhibition of plaque formation or cytopathology with laboratory strains of CMV; clinical isolates of CMV were up to 8 times less sensitive. 50% inhibition of HIV replication in vitro occurred with foscarnet 10 to 29.7 jimol/L. HIV multiplication, assessed by expression of p15 and p24 proteins in vitro, was inhibited by foscarnet concentrations > 150 jLtmol/L. HIV p24 antigen levels were also significantly reduced in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex during foscarnet induction therapy.

In vitro additive or synergistic activity has been seen with foscarnet plus various other antiviral drugs, including ganciclovir or zidovudine against CMV isolates, and zidovudine or dideoxythymidine against HIV isolates. The additive effect against HIV isolates was also seen in vivo in patients with HIV infection.

Resistance to foscarnet has been shown to develop in vitro in herpes simplex virus (HSV), HIV and, more rarely, CMV isolates. Clinical isolates of HSV and CMV resistant to foscarnet have also been reported. Cross-resistance can occur between foscarnet and aciclovir.

Pharmacokinetic Properties

Since foscarnet is poorly absorbed following oral administration, the drug is generally given by intravenous infusion. There are wide interindividual variations in plasma concentrations following infusion, possibly because of foscarnet deposition in bone and cartilage.

Almost 90% of a foscarnet dose is excreted unchanged in the urine. The long terminal phase elimination half-life of foscarnet (up to mean 88 hours) is assumed to be the result of sequestration of the drug into bone, but the shorter first and second phase half-lives (up to 1.4 and 6.8 hours) mean that continuous or frequent short infusions are required to maintain adequate plasma drug concentrations. Plasma foscarnet clearance decreases and elimination half-life increases with reductions in renal function.

Therapeutic Use

Several noncomparative and comparative studies have established the efficacy of foscarnet given to patients with CMV retinitis and AIDS, formerly as continuous but now more commonly as intermittent (every 8 hours) intravenous infusions. Dosages of 180 to 230 mg/kg/day were given in the induction phase (2 to 4 weeks) and 60 to 130 mg/kg (once daily) were given for 5 to 7 days/week in the maintenance period (3 to 95 weeks). A complete or partial clinical response was seen in 89 to 100% of patients during the induction phase and in up to 60% of patients during maintenance. Successful foscarnet treatment of patients with CMV retinitis and AIDS has also been reported after intravitreal administration.

Rates of response were similar for patients with CMV retinitis and AIDS receiving foscarnet as intravenous induction therapy in 3-times-daily or twice-dailyregimens. The period of remission during maintenance treatment (1 month with lower dosages) was extended with higher dosages (120 mg/kg/day) in some patients. Relapses responded to further foscarnet treatment, but the duration of remission appeared to decrease with time. Survival in patients receiving foscarnet for CMV retinitis and AIDS may also be dependent on the dosage of maintenance foscarnet therapy: patients in a small study receiving 120 mg/kg/day survived for significantly longer than those receiving 90 mg/kg/day.

Several trials comparing the efficacy of intravenous foscarnet and ganciclovir in the treatment of patients with CMV retinitis and AIDS have found no significant differences between treatments in the number of patients achieving remission or the time to relapse during maintenance therapy. However, in one study, foscarnet recipients had a survival advantage over ganciclovir recipients; after 19 months of treatment, a significant difference in mortality rate was observed, with 49% of 127 ganciclovir recipients alive compared with 66% of 107 foscarnet recipients.

Foscarnet and ganciclovir were successfully administered in combination to patients with AIDS and CMV retinitis or gastrointestinal infections previously unresponsive to either drug alone, and to patients infected with several strains of CMV with different susceptibilities. Complete or partial responses were seen in 75 to 100% of patients.

Foscarnet has also been used alone as therapy for CMV infections of the gastrointestinal tract. Partial or complete responses were seen in 67 to 100% of patients, depending on the site of the infection.

Clinical improvement was seen in about 50% of bone marrow transplant recipients receiving intravenous foscarnet 69 to 300 mg/kg/day for 2 weeks for CMV infection. CMV interstitial pneumonia appears to be unresponsive to foscarnet therapy. CMV-associated marrow suppression in bone marrow transplant recipients was reduced during treatment with foscarnet 60 mg/kg 3 times daily for 2 weeks but recurred in most patients on withdrawal of foscarnet. Similarly, while prophylaxis with foscarnet in CMV-seropositive patients about to undergo bone marrow transplantation suppressed infection during treatment, the limited data available suggest that CMV infection occurs readily post-treatment.

Aciclovir-resistant HSV infections in immunocompromised patients have been successfully treated with intravenous foscarnet 120 to 200 mg/kg/day for up to 4 weeks according to case reports. In a series of 26 patients, a clinical response was seen in 21, and complete re-epithelialisation in 19. Maintenance foscarnet treatment (40 mg/kg/day for 8 weeks) in patients with recurring aciclovir-resistant HSV infections increased the recurrence-free period over that seen in patients receiving no maintenance therapy.

Foscarnet has also been used successfully to treat varicella zoster virus (VZV) infections resistant to aciclovir in some but not all case reports. Similarly, foscarnet treatment of patients with chronic hepatitis B infection was successful in 1 of 2 case reports. However, there are several reports of patients with fulminant hepatitis B infection responding to foscarnet therapy.

Tolerability

The most frequent dose-limiting adverse effect of foscarnet therapy in early trials, most of which used continuous administration and failed to provide adequate hydration, was a 2- to 3-fold increase in serum creatinine levels in about 45% of patients. The nephrotoxicity appears to be caused by tubular necrosis and is usually reversible on withdrawal of foscarnet. Renal dysfunction can be minimised by adjusting the dosage of foscarnet according to serum creatinine levels, maintaining adequate hydration, using intermittent rather than continuous infusion and avoiding concomitant administration of other potentially nephrotoxic drugs.

Foscarnet causes anaemia in 20 to 50% of patients, but does not appear to be associated with neutropenia. Gastrointestinal adverse effects occur in 20 to 30% of recipients. Electrolyte changes, including hyper- and hypocalcaemia, hypo-kalaemia and hypomagnesaemia (15 to 43% of patients), and hyper- and hypo-phosphataemia (6 to 8%), have been documented with foscarnet therapy. Convulsions have been recorded in 10% of patients receiving foscarnet and there are a number of reports of penile and vulval ulceration (3 to 9% of patients) associated with the drug.

The tolerability profiles of foscarnet and ganciclovir are different, allowing substitution in patients intolerant of one drug or the other. The use of foscarnet in patients unable to tolerate concomitant ganciclovir and zidovudine because of neutropenia appears particularly promising. Foscarnet and ganciclovir in normal or reduced dosage regimens were well tolerated in the few patients receiving the combination.

Dosage and Administration

In patients with AIDS and CMV infection, foscarnet induction therapy is given as a 1- to 2-hour infusion of 60 mg/kg every 8 hours or 90 to 100 mg/kg every 12 hours for 2 to 4 weeks. This is followed by maintenance therapy of daily 2-hour infusions of foscarnet 90 to 120 mg/kg in patients with CMV retinitis. Foscarnet dosages must be adjusted according to renal function. Intravitreal administration to patients with CMV retinitis has been reported.

Infusions of foscarnet 120 to 200 mg/kg/day for up to 4 weeks are given for aciclovir-resistant herpes virus infections.

Monitoring of serum creatinine and electrolyte levels is necessary and foscarnet infusions should be accompanied by saline hydration to minimise the risk of acute renal damage. The incidence of genital ulceration may be minimised by thorough personal hygiene after micturition.

Concomitant use of foscarnet with potentially nephrotoxic drugs (e.g. aminoglycosides, cyclosporin, amphotericin B) or agents likely to affect serum calcium levels (e.g. pentamidine) requires close monitoring.

Various sections of the manuscript reviewed by: J. Aschan, Karolinska Instituted Institutionen för Medicin, Huddinge Sjukhus, Huddinge, Sweden; Y. Becker, Department of Molecular Virology, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; C. Birch, Victorian Infectious Diseases Reference Laboratory, Fairfield Hospital, Fairfield, Victoria, Australia; S. Cox, Department of Virology, Swedish Institute for Infectious Disease Control, Stockholm, Sweden; M.M. Fanning, Division of Infectious Diseases, The Wellesley Hospital, Toronto, Ontario, Canada; B.G. Gazzard, Chelsea and Westminster Hospital, London, England; S.A. Geier, Klinikum Innenstadt, Medizinische Poliklinik, Ludwig-Maximilians-Universität, Munich, Germany; A.f.H. Hall, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; D.A. Jabs, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; M.A. Jacobson, AIDS Program–UCSF, Clinical Research Section, San Francisco General Hospital, San Francisco, California, USA; C. Katlama, Service des Maladies Infectieuses, Parasitaires et Tropicales, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; D.J Morris, Division of Virology, Department of Pathological Sciences, University of Manchester Medical School, Manchester, England; M.A. Polis, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA; A. Stoehr, Allgemeines Krankenhaus St Georg, Hamburg, Germany