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PubMed1998

Incidence of foscarnet resistance and cidofovir resistance in patients treated for cytomegalovirus retinitis. The Cytomegalovirus Retinitis and Viral Resistance Study Group.

Cytomegalovirus (CMV) retinitis is a common opportunistic infection in patients with AIDS. With long-term therapy for CMV retinitis, resistant CMV may develop. In a prospective study of 122 patients with CMV retinitis, 2.4 and 0.8% of patients had foscarnet-resistant blood culture isolates (50% inhibitory concentration [IC50], >400 microM) and urine culture isolates, respectively, at diagnosis of CMV retinitis prior to treatment, whereas 4.1 and 6.6% had cidofovir-resistant (IC50, >2 microM) blood and urine culture isolates, respectively. Patients were treated according to best medical judgement. Of 44 foscarnet-treated patients, 26% had a resistant blood or urine culture isolate by 6 months of treatment and 37% had a resistant isolate by 9 months; of 13 cidofovir-treated patients, 29% had a resistant blood or urine culture isolate by 3 months of therapy. The probabilities of developing foscarnet resistance while on foscarnet and developing cidofovir resistance while on cidofovir were not significantly different from that for developing ganciclovir resistance while on ganciclovir (odds ratios, 1.87 [P = 0.19] and 2.28 [P = 0.15], respectively).

Adult↗
PubMed2006

Role of helix P of the human cytomegalovirus DNA polymerase in resistance and hypersusceptibility to the antiviral drug foscarnet.

Mutations in the human cytomegalovirus DNA polymerase (UL54) can not only decrease but also increase susceptibility to the pyrophosphate (PP(i)) analogue foscarnet. The proximity of L802M, which confers resistance, and K805Q, which confers hypersusceptibility, suggests a possible unifying mechanism that affects drug susceptibility in one direction or the other. We found that the polymerase activities of L802M- and K805Q-containing mutant enzymes were literally indistinguishable from that of wild-type UL54; however, susceptibility to foscarnet was decreased or increased, respectively. A comparison with the crystal structure model of the related RB69 polymerase suggests that L802 and K805 are located in the conserved alpha-helix P that is implicated in nucleotide binding. Although L802 and K805 do not appear to make direct contacts with the incoming nucleotide, it is conceivable that changes at these residues could exert their effects through the adjacent, highly conserved amino acids Q807 and/or K811. Our data show that a K811A substitution in UL54 causes reductions in rates of nucleotide incorporation. The activity of the Q807A mutant is only marginally affected, while this enzyme shows relatively high levels of resistance to foscarnet. Based on these data, we suggest that L802M exerts its effects through subtle structural changes in alpha-helix P that affect the precise positioning of Q807 and, in turn, its presumptive involvement in binding of foscarnet. In contrast, the removal of a positive charge associated with the K805Q change may facilitate access or increase affinity to the adjacent Q807.

Amino Acid Sequence↗
PubMed1991

Foscarnet sodium.

Cytomegalovirus (CMV), a major opportunistic viral pathogen frequently causing disease in immunocompromised patients such as organ transplant recipients and people with AIDS, may present as pneumonitis, gastrointestinal disease, or encephalitis. Its most common manifestation in patients with AIDS is retinitis which, if left untreated, invariably progresses to extensive retinal necrosis and ultimately to blindness. Ganciclovir sodium, currently the only licensed antiviral agent for the treatment of CMV retinitis, effectively controls this infection in a majority of AIDS patients, but significant granulocytopenia or thrombocytopenia related to ganciclovir therapy often limit its clinical application. Myelosuppression may be further exacerbated in AIDS patients by such other agents as zidovudine or trimethoprim/sulfamethoxazole, often necessitating dosage reductions or discontinuation of these agents in patients receiving ganciclovir. Foscarnet sodium, a pyrophosphate analog active against both cytomegalovirus and the human immunodeficiency virus type 1 (HIV), may be an effective alternative to ganciclovir in the management of CMV retinitis. Trials with intravenous foscarnet in CMV retinitis have reported favorable results using initial daily doses of 180-230 mg/kg/d given as intermittent infusions every eight hours, followed by maintenance regimens of 60-90 mg/kg/d given as single daily one- or two-hour infusions. Foscarnet therapy may result in renal impairment, and indefinite intravenous maintenance therapy may be required to prevent recurrence of CMV infection. Despite these drawbacks, foscarnet's lack of major myelosuppressive toxicity, and its activity in suppressing HIV replication, make this a potentially safe and effective alternative agent for the management of CMV infection, especially in AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial.

STUDY OBJECTIVE: To determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe mucocutaneous disease due to acyclovir-resistant herpes simplex virus type-2 (HSV-2) infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Open-labeled drug administration to patients with AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection. SETTING: Medical floors of acute care hospital. PATIENTS: Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2. INTERVENTION: Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days. MEASUREMENT AND MAIN RESULTS: All patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces. CONCLUSION: Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.

Acquired Immunodeficiency Syndrome↗
PubMed1991

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS: Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION: PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS: PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS: The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS: The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

Acquired Immunodeficiency Syndrome↗
PubMed1998

[Treatment of CMV retinitis with intravitreal foscarnet].

PURPOSE: To assess the tolerability and efficacy of intravitreal injections of foscarnet in cytomegalovirus (CMV) retinitis in acquired immunodeficiency syndrome (AIDS). METHODS: Patients with CMV retinitis resistant and/or intolerant to intravenous foscarnet and ganciclovir and resistant to intravitreal ganciclovir were included. The induction therapy consisted of intravitreal injections of 2,400 micrograms of foscarnet twice a week. The assessment was performed by clinical examination and photographies of the fundus. RESULTS: Three patients (four eyes) have been included. Three eyes were administered seven and one eye eight intravitreal injections. The tolerability was good, but the efficacy was mere: the retinal lesions became less edematous, but they still extended. CONCLUSION: In these four eyes with CMV retinitis resistant to intravitreal ganciclovir, intravitreal injections of foscarnet were well tolerated but did not stop the progression of the retinitis.

AIDS-Related Opportunistic Infections↗
PubMed1991

Approaches to the treatment of cytomegalovirus retinitis: ganciclovir and foscarnet.

Both ganciclovir, a nucleoside analogue, and foscarnet, a pyrophosphate analogue, specifically bind cytomegalovirus (CMV) DNA polymerase and inhibit CMV replication at plasma concentrations achievable with intravenous administration. The agents have similar plasma half-lives, and both are cleared solely by the kidneys. Foscarnet has a low solubility and a high degree of ionization at physiologic pH, requiring it to be administered in higher doses and larger volumes. Both drugs are administered as an initial induction regimen followed by a long-term maintenance regimen. Among patients with the acquired immune deficiency syndrome (AIDS) who have CMV retinitis, the efficacy of long-term maintenance therapy, as measured by median time to retinitis progression, appears to be similar for the two drugs. The major toxicity of ganciclovir is myelosuppression, with dose-limiting neutropenia occurring in approximately 16% and thrombocytopenia in 5% of AIDS patients. The major toxicity of foscarnet is nephrotoxicity, with dose-limiting toxicity occurring in approximately 10-23% of patients; other effects of foscarnet include hypocalcemia, which may be associated with seizure and arrhythmia. Studies in vitro indicate an additive or synergistic inhibitory effect on CMV when these two drugs are combined, suggesting that lower-dose combination regimens or higher-dose alternating regimens may result in greater efficacy with less toxicity than with either drug alone.

Antiviral Agents↗
PubMed1985

Clinical experiences with phosphonoformate (foscarnet) treatment of viral diseases following renal transplantation.

The effect of the antiviral drug phosphonoformate (Foscarnet) was studied in 32 patients following renal transplantation. Viral diagnosis was verified in 29 of 33 episodes of suspected clinical virosis. The clinical effect of Foscarnet was good in 12 of 14 primary cytomegalovirus infections. In 5 of 7 varicella-zoster virus, in 4 of 6 secondary cytomegalovirus and in 2 herpes simplex virus (type 1; type 2) infections the effect of the treatment was clinically judged as good. The beneficial effect could in these patients be overestimated as the natural courses of the viral infections were unknown. No clinical side effects of Foscarnet were found. Clinically unimportant changes in s-calcium were noted in 6 patients. The dosage of Foscarnet was increased during the study. At present an initial bolus dose followed by 14 days of parenteral infusions can be recommended.

Adult↗
PubMed1994

Early treatment of CMV infections in allogeneic bone marrow transplant recipients with foscarnet or ganciclovir.

Twenty-five patients with hematologic malignancies (n = 21) or aplastic anemia (n = 4) undergoing an allogeneic BMT from an HLA-identical sibling developed cytomegalovirus (CMV) antigenemia at a mean interval from BMT of 41 days (range 16-141 days). All patients were treated at the time of antigenemia in the absence of other signs of CMV disease with ganciclovir (n = 13) or foscarnet (n = 12) if the WBC count was < 2.5 x 10(9)/l or the patient had aplastic anemia. The two groups were comparable for age, sex and disease status. There were more patients receiving T cell-depleted grafts in the foscarnet group (58% vs 15%, p = 0.003). The first course of treatment was planned to last a minimum of 10 days: foscarnet was given at 180 mg/kg/day, and ganciclovir at 10 mg/kg/day. Patients still showing pp65-positive cells continued treatment in the absence of adverse effects such as cytopenia and/or increased creatinine levels. Maintenance treatment was given for 3-4 weeks. End-points of the study were (1) clearing of CMV antigenemia, (2) tolerance and side-effects, and (3) progression to CMV disease. Both agents were effective in clearing CMV antigenemia: 14 of 25 patients were CMV antigen-negative by day 14 of treatment and all surviving patients were negative by day +50. Renal toxicity was seen mainly in the foscarnet group but caused discontinuation of the drug only in one patient. Myelotoxicity was seen in the ganciclovir group and again could be controlled in 12 of 13 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome].

A 41-year-old man with acquired immunodeficiency syndrome (AIDS) developed cytomegalovirus (CMV) retinitis. Intravenous administration of ganciclovir arrested progression of the retinitis, but it was discontinued due to side effects of severe anemia, neutropenia, and thrombocytopenia. Reactivation of CMV retinitis occurred two weeks after stopping ganciclovir, and then forscarnet was given intravenously. The response was prompt with resolution of the retinitis. There was no progression of retinitis during the treatment. The patient experienced renal dysfunction as a side effect of foscarnet, but it was reversible. As with ganciclovir, foscarnet appeared to be an effective drug for CMV retinitis associated with AIDS. Both drugs have severe adverse events: foscarnet causes renal dysfunction and ganciclovir causes myelosuppression, that necessitated discontinuation of the therapy. We suggest that alternating ganciclovir and foscarnet administration, switching to other treatment on the basis of the clinical response and side effects of the drugs, is an efficacious regimen for the treatment of CMV retinitis associated with AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1993

Successful foscarnet therapy for acyclovir-resistant mucocutaneous infection with herpes simplex virus in a recipient of allogeneic BMT.

A 41-year-old recipient of matched unrelated BMT acquired a severe mucocutaneous herpes simplex virus (HSV) type I infection during acyclovir prophylaxis. He was subsequently treated with high-dose acyclovir, but the HSV infection continued. In vitro analysis of the HSV isolate, obtained before and after the administration of high-dose acyclovir, demonstrated marked resistance to acyclovir but sensitivity to the antiviral agent foscarnet. The mucocutaneous HSV infection healed completely to a 16 day course of foscarnet. However, relapse of the acyclovir-resistant HSV infection occurred 202 days after the first foscarnet treatment but he responded again to a second foscarnet course. These data indicate that, with the rising frequency of acyclovir-resistant HSV infections observed in immunocompromised hosts, viral isolates should be tested for susceptibility to different antiviral drugs in recipients of BMT with recurrent or persistent HSV infections.

Acyclovir↗
PubMed1996

Foscarnet for pre-emptive therapy of CMV infection detected by a leukocyte-based nested PCR in allogeneic bone marrow transplant patients.

Fifteen allogeneic BMT patients in a phase II study were given foscarnet 60 mg/kg twice daily for 14 days as pre-emptive therapy against CMV disease. CMV infection was diagnosed by a leukocyte-based nested PCR. All 15 patients were evaluable for toxicity. One patient did not fulfill the inclusion criteria of two consecutively positive CMV PCR tests and therefore was not evaluable for efficacy. Thus, 14 of 15 patients were evaluable for development of CMV disease. None of the patients developed CMV disease and all 14 assessable patients had a negative CMV isolation at the end of therapy. None of the 15 patients had to discontinue therapy due to toxicity. Six patients reported mild gastrointestinal disturbances, three patients headaches, and three patients mild urethritis or hemorrhagic cystitis. Serum-electrolyte disturbances were common including abnormal magnesium, potassium and calcium levels. Two patients developed mild serum-creatinine increases requiring adjustment of the foscarnet dosage according to protocol. We conclude that a dosage of foscarnet of 60 mg/kg given twice daily seems to be safe and effective in preventing CMV disease in allogeneic BMT recipients. A study comparing foscarnet and ganciclovir is indicated.

Adolescent↗
PubMed1996

Combined foscarnet -ganciclovir treatment for cytomegalovirus infections after allogeneic hemopoietic stem cell transplantation (Hsct).

Thirty two allogeneic bone marrow transplant (BMT) recipients, aged 16-55 (median 35), with CMV antigenemia (= > 5 positive cells) developing at a median interval from BMT of 49 days, were given combined treatment with foscarnet and ganciclovir for 15 days. Maintenance was given with foscarnet and ganciclovir on alternate days for an additional 2 weeks. 31/32 patients were on cyclosporin 30 on systemic antibiotics and 9 were on intravenous amphotericin Median laboratory values on day 1 and 15 of treatment were respectively creatinine 1.0-1.1 mg%; WBC 5.7-4.1 x 10(9)/l; platelets 78 72 x 10(9)/l. All patients cleared CMV-antigenemia by day +15, though 5 reactivated on and 14 off maintenance: the dose of foscarnet (but not ganciclovir) received in the first 15 days was significantly lower in patients reactivating within 30 days (p = 0.0002). Six patients died, one with i.p., one with multiorgan failure, and four with infections. Eighteen patients survive 119-1051 days post-transplant. The actuarial TRM at 1 year is 23%. This study shows that combined foscarnet-ganciclovir is one therapeutic option for allogeneic BMT recipients developing CMVAg-emia with a high number of CMVAg+ cells: treatment can be given together with cyclosporin and antibiotics with appropriate dose reductions; it produces prompt clearing of CMV infection, and may reduce transplant related mortality when compared to single agent therapy.

Adolescent↗
PubMed1998

Suppression of HHV-8 viremia by foscarnet in an HIV-infected patient with Kaposi's sarcoma and HHV-8 associated hemophagocytic syndrome.

Human herpes virus 8 (HHV-8) seems to be involved in the pathogenesis of Kaposi s sarcoma. In vitro, antiviral drugs with activity against herpes viruses also can suppress HHV-8, however, little is known about the antiviral activity against HHV-8 in vivo. In this report we describe the effects of foscarnet on HHV-8 viremia in an HIV-infected patient with disseminated Kaposi s sarcoma and a presumably HHV-8 associated hemophagocytic syndrome. HHV-8 DNA could be detected in this patient by PCR in peripheral blood mononuclear cells (PBMC), in bronchoalveolar fluid and tumor biopsies. After initiation of foscarnet because of a severe hemophagocytic syndrome HHV-8 PCR turned negative in PBMC, but stayed positive in pleural effusions and in a tumor biopsy. After termination of foscarnet therapy HHV-8 DNA in PBMC persistently reappeared. Under treatment with foscarnet the hemophagocytic syndrome dramatically improved, suggesting that HHV-8 had a pathogenetic role in this syndrome.

AIDS-Related Opportunistic Infections↗
PubMed1989

Successful treatment of progressive acyclovir-resistant herpes simplex virus using intravenous foscarnet in a patient with the acquired immunodeficiency syndrome.

We report a case of orofacial herpes simplex virus (HSV) infection that was progressive despite multiple courses of acyclovir sodium in a patient with the acquired immunodeficiency syndrome. The viral isolate was shown to be resistant to acyclovir in vitro, but proved susceptible to vidarabine and foscarnet sodium (trisodium phosphonoformate). The patient failed to respond to a 2-week course of intravenous vidarabine. However, rapid improvement in the orofacial lesion occurred with intravenous foscarnet. Most HSV isolates that are resistant to acyclovir are spontaneous mutants partially or completely lacking in thymidine kinase. Because foscarnet is a direct inhibitor of HSV DNA polymerase, this compound is expected to have efficacy against acyclovir-resistant strains. This report documents successful treatment of clinically significant HSV with intravenous administration of foscarnet, suggesting that further study is indicated.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Foscarnet therapy in chronic hepatitis B virus E antigen carriers.

Foscarnet (trisodium phosphonoformate) is a novel antiviral agent that inhibits viral-specific DNA polymerase. In the present study, eight males with chronic HBV carriage (HBeAg and HBV-DNA seropositivity greater than 12 months) showing chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH) on liver biopsy received either a continuous infusion of foscarnet at 0.15 mg/kg/min for 7 days or 180 mg/kg/day divided into three daily boluses for 2 weeks. In all eight, HBV-DNA levels fell during therapy (median, 401 pg/40 microliters serum; range, 4-3, 100) vs. pretreatment levels (median, 533 pg/40 microliters; range, 30-4, 175), but in none was HBV-DNA undetectable at any stage. Within 1 month, the HBV-DNA had risen to pretreatment levels in all but one patient (with the lowest pretreatment level), who cleared HBeAg and developed anti-HBe within 3 months. Two further patients were anti-HBe positive at 6 months, but their pretreatment serum HBV-DNA levels were already low, suggesting a high probability of spontaneous seroconversion. Toxicity was not evident with the continuous infusion, but for those receiving IV bolus therapy, serum creatinine and phosphate levels rose in three of four patients, necessitating a 25% dose reduction. There was no difference in the effect on serum HBV-DNA between the two regimes. We conclude that foscarnet has only modest antiviral activity in chronic HBV carriers.

Adult↗
PubMed1988

Toxicity of intravitreal injection of foscarnet in the rabbit eye.

Foscarnet (sodium phosphonoformate) is an antiviral with a high degree of efficacy against members of the herpes simplex virus family. We studied the toxicity of single doses of intravitreally administered foscarnet in the albino rabbit. Eyes were evaluated clinically and by light microscopy. Data demonstrated that doses ranging from 20 to 1000 micrograms per 0.1 milliliter are nontoxic to the retina, suggesting that foscarnet may be useful in the treatment of acute retinal necrosis and cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.

Animals↗
PubMed1992

Combined and alternating ganciclovir and foscarnet in acute and maintenance therapy of human immunodeficiency virus-related cytomegalovirus encephalitis refractory to ganciclovir alone. A case report and review of the literature.

Cytomegalovirus (CMV) causes life-threatening disseminated infections and in particular vision-threatening infections of the retina in patients with the acquired immunodeficiency syndrome. Ganciclovir currently represents the most frequently used therapy for CMV retinitis. However, cases of ganciclovir-resistant CMV strains have been described, in which foscarnet seems to be an effective alternative. Both drugs have serious toxicities, and relapses frequently occur during maintenance therapy. In a patient with CMV encephalitis, we administered a 3-week combination ganciclovir/foscarnet induction therapy (ganciclovir 5 mg/kg every 12 h; foscarnet 60 mg/kg every 8 h), followed by an alternating maintenance administration of both drugs every other day (ganciclovir 5 mg/kg, foscarnet 120 mg/kg) to reduce toxicity and resistance. This regimen was tolerated well and seemed to be more effective than ganciclovir alone in a patient with CMV encephalitis.

Acquired Immunodeficiency Syndrome↗