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[Efficacy of cidofovir in an HIV infected patient with an acyclovir and foscarnet resistant herpes simplex virus infection].

BACKGROUND: We report the case of an AIDS patient, whose persistant HSV2 ulceration was clinically and phenotypically resistant to acyclovir and foscarnet. Only five clinical isolates of simultaneous acyclovir and foscarnet resistance have been previously described. CASE REPORT: This patient, without history of opportunistic infection, was hospitalized for a recurrent scrotal ulceration resistant to several antiviral treatment such as acyclovir, valacyclovir or foscarnet. The CD4 count was stable at 150/mm(3) and the HIV viral load was below detection level. The last recurrence appeared rapidly under valacyclovir therapy which had been introduced after 65 days of foscarnet therapy. Thus, the patient received a new dose of foscarnet. After initial efficacy, the ulceration increased once again. HSV2 phenotypic determination was done and detected, at that time, a double resistance to acyclovir and foscarnet. Healing was obtained with intravenous cidofovir. DISCUSSION: Foscarnet and acyclovir resistance in an HSV2 isolate is rare. This report presents several particularities. First, whereas the earlier published patients with an acyclovir and foscarnet resistant strain were widely immunocompromised, this was not the case for our patient. Secondly, in contrast with most precedent observations in which acyclovir-resistant strain disappeared after foscarnet therapy, in our case the acyclovir resistant strain remained after foscarnet therapy. Finally, few reports concerned the clinical efficacy of cidofovir in HSV infection. In this case, we proved that intravenously cidofovir was highly and rapidly effective on acyclovir and foscarnet resistant strains.

AIDS-Related Opportunistic Infections↗

Ocular iontophoretic supplementation of intravenous foscarnet therapy.

PURPOSE: Reactivation of cytomegalovirus retinopathy during intravenous antiviral therapy is usually treated with higher doses of drug. We sought to determine whether ocular iontophoresis increases the intravitreal foscarnet concentration attained by intravenous injection. METHODS: We injected foscarnet (120 mg/kg or 180 mg/kg) intravenously into 24 rabbits and determined the time of maximal concentrations in serum and vitreous humor. We injected the same doses into 24 additional rabbits and administered ocular foscarnet iontophoresis one hour later. Vitreous humor concentrations were assayed at one, four, eight, 24, 60, and 120 hours after iontophoresis and compared with those from injection alone. RESULTS: Maximum serum and vitreous humor concentrations were achieved one hour after each intravenous dose. Maximum vitreous humor concentrations were achieved four hours after 120 mg/kg intravenous doses plus iontophoresis and eight hours after 180-mg/kg intravenous doses plus iontophoresis. Vitreous humor levels were significantly higher in eyes receiving intravenous foscarnet (120 mg/kg, P < .0001; 180 mg/kg, P < .0001) plus ocular Foscarnet iontophoresis than in those receiving intravenous foscarnet alone. Vitreous humor foscarnet levels in eyes receiving 120 mg/kg intravenously did not differ significantly from those in the group receiving 180 mg/kg intravenously (P < .1). The intravenous dose did not significantly affect vitreous humor levels after iontophoresis (P < .1). Vitreous concentrations fell below therapeutic levels (25 microM) in all eyes 60 hours after intravenous foscarnet and ocular foscarnet iontophoresis. CONCLUSIONS: Ocular iontophoresis significantly increased intravitreous foscarnet concentrations above those attained by intravenous injection alone and may be an effective alternative to increasing the intravenous drug dose in patients with reactivated cytomegalovirus retinopathy.

Animals↗

Foscarnet nephrotoxicity: mechanism, incidence and prevention.

Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of foscarnet-induced nephrotoxicity as most data comes from recipients of renal allografts or from patients with severe underlying disease or with other nephrotoxic drugs. We have retrospectively analyzed the evolution of renal function after 56 courses of foscarnet. In addition, we have prospectively studied the protective effects of hydration on foscarnet nephrotoxicity (2.5 liters of saline/day during the night before the foscarnet therapy and throughout the course of treatment). Foscarnet-induced acute renal failure was defined as a rise in serum creatinine of at least 25% from the basal value. An increase in serum creatinine occurred in 37 cases out of the 56 courses of foscarnet (66%). The mean serum creatinine prior to foscarnet was 80.5 +/- 3.3 mumol/l and the mean increase was 190 +/- 28.3 mumol/l (range 80-1,000). Peak serum creatinine was higher than 200 and 300 mumol/l in 16 and 13 patients, respectively. Kidney obtained at autopsy from a 30-year-old male with AIDS, CMV pneumonitis and acute renal failure secondary to foscarnet administration showed an extensive tubular necrosis. In the group which was prospectively hydrated only 1 patient had an acute renal failure. The mean serum creatinine at the peak (96 +/- 4 mumol/l) and at the end of the treatment (83 +/- 4 mumol/l) was significantly lower (p less than 0.05) than in non hydrated patients. In conclusion, foscarnet is a highly nephrotoxic drug which induces acute tubular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

The effect of foscarnet (phosphonoformate) on human immunodeficiency virus isolation, T-cell subsets and lymphocyte function in AIDS patients.

Foscarnet was administered by continuous intravenous infusion in 15 patients with the acquired immunodeficiency syndrome (AIDS) in an open, uncontrolled study. Mean steady state serum concentrations of foscarnet was 261 mumol/l. Treatment was given for 6-21 days, median 14 days, being interrupted prematurely due to renal function impairment in seven patients, and due to other reasons in three patients. Foscarnet therapy was accompanied by improvement of some, probably cytomegalovirus (CMV) related, symptoms but did not otherwise affect the clinical condition of the patients. The occurrence of positive CMV cultures decreased significantly during therapy. Human immunodeficiency virus (HIV) detection by culture was positive in 70-80% of cultures and was unaffected by foscarnet treatment. Eight patients had detectable, free HIV antigen in serum before therapy, and in five of these HIV antigen disappeared during therapy, but reappeared 4-23 weeks after therapy. No patient lost HIV antigen, except during foscarnet therapy. No patient became HIV antigen positive during foscarnet therapy. Immunological parameters did not change during or after foscarnet therapy. Renal function impairment was seen in 9 patients (95% confidence limits, 32-84%), apparently due to reversible tubular damage. At follow-up, serum creatine was normal in all surviving patients. Concomitant medication may have contributed to the renal side-effects. Severe renal function impairment, i.e. serum creatinine above 0.25 mumol/l, was only seen in patients who at the start of foscarnet therapy were chronically affected by their disease. Thus, foscarnet reduces HIV antigen production in AIDS patients. Renal function impairment limits foscarnet use in AIDS patients, but in individuals with less severe manifestations of HIV infection, this side effect may be less frequent.

Acquired Immunodeficiency Syndrome↗

Characterisation of foscarnet-resistant strains of human immunodeficiency virus type 1.

Foscarnet is a broad-spectrum viral DNA polymerase inhibitor active in vitro and in vivo against human immunodeficiency virus type 1 (HIV-1). Strains of HIV-1 resistant to foscarnet were selected by in vitro passage in increasing concentrations of drug. Reduced susceptibility to foscarnet was evident at the levels of both HIV-1 replication and reverse transcriptase. Biologically cloned, foscarnet-resistant strains with distinct genotypes were hypersensitive to zidovudine, azidodeoxyuridine, nevirapine, and R82913 but had unchanged susceptibility to zalcitibine and didanosine. The reverse transcriptase of foscarnet-resistant strains had unique substitutions Glu89-Lys, Leu92-Ile, or Ser156-Ala, the third being associated with six polymorphic changes. Introduction of these mutations into wild-type HIV-1 by site-directed mutagenesis confirmed their role in foscarnet resistance. In the three-dimensional structure of the reverse transcriptase enzyme these amino acids are located close to the template strand of the template primer and far away from the putative pyrophosphate binding site, suggesting that the mechanism by which HIV-1 becomes resistant to foscarnet is indirect. Foscarnet resistance is thus likely to be mediated through an altered interaction of the mutant enzyme with the template strand of the template primer which distorts the geometry of the polymerase active site and thereby decreases foscarnet binding.

Amino Acid Sequence↗

Increased survival of a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis who received sodium phosphonoformate (foscarnet).

PURPOSE: To evaluate the impact of foscarnet on the longevity of persons with human immunodeficiency virus, type 1 (HIV-1) infection and cytomegalovirus (CMV) retinitis. PATIENTS AND METHODS: A cohort of 24 patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis received sodium phosphonoformate (foscarnet) as part of a controlled efficacy trial at the National Institutes of Health. Foscarnet was continued for as long as it was tolerated. Antiretroviral therapy was given to the patients as tolerated. Long-term follow-up was available on all patients. RESULTS: Seventeen patients received zidovudine during or after receiving foscarnet, 2 patients received dideoxyinosine, 2 patients zidovudine and dideoxyinosine, and 3 patients received no specific antiretroviral agent. Patients received foscarnet for a mean of 6.2 months (median, 4 months; range, 10 days to 22 months). Ten patients required a change to ganciclovir therapy at some time after receiving foscarnet. The median time from the diagnosis of CMV retinitis until death was 13.5 months (range, 3 to 34 months). Patients lived longer than untreated or ganciclovir-treated historical controls with AIDS and CMV retinitis. There was no difference in the survival of patients treated with foscarnet at the time of diagnosis and those patients treated with foscarnet only after progression of their CMV retinitis. CONCLUSIONS: These data suggest that foscarnet may prolong the survival of persons with AIDS and CMV retinitis and should be the initial treatment of choice in these patients.

Acquired Immunodeficiency Syndrome↗

The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH < 2.0) prior to administration of ranitidine and increased gastric pH (pH > 6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 microM) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P < 0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.

Administration, Oral↗

A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.

BACKGROUND AND METHODS: Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both foscarnet and vidarabine. We conducted a randomized trial to compare foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine. RESULTS: The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after foscarnet was discontinued. CONCLUSIONS: For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.

Acquired Immunodeficiency Syndrome↗

Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis.

BACKGROUND AND METHODS: We performed a multicenter, randomized, unblinded clinical trial (the Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial) designed to compare ganciclovir with foscarnet in the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Of 234 patients, 127 were randomly assigned to ganciclovir and 107 to foscarnet; the study drugs were administered according to a common protocol at the 11 participating clinical centers. Antiretroviral therapy (with zidovudine, didanosine, or dideoxycytidine) was given as dictated by best medical judgment. The patients were followed for the progression of retinitis, visual loss, and death. RESULTS: Excess mortality in the ganciclovir group (as compared with the foscarnet group) led the Policy and Data Monitoring Board to recommend suspension of the treatment protocol 19 months after the trial started. As of that time, 65 of the patients assigned to ganciclovir had died, as compared with 36 of those assigned to foscarnet (51 percent vs. 34 percent, P = 0.007; relative risk, 1.79; 95 percent confidence interval, 1.17 to 2.73). The median survival was 8.5 months in the ganciclovir group and 12.6 months in the foscarnet group. Although the patients assigned to ganciclovir received less antiretroviral therapy on average than those assigned to foscarnet, the excess mortality could not be explained entirely by differences in exposure to antiretroviral drugs. In the forscarnet group, the only subgroup of patients identified as having excess mortality were those whose renal function was compromised at entry. There was no difference between the two treatment groups in the rate of progression of retinitis (relative risk, 0.95; P = 0.751). CONCLUSIONS: These results suggest that for patients with AIDS, and cytomegalovirus retinitis, treatment with foscarnet offers a survival advantage over treatment with ganciclovir, although the patients may not tolerate foscarnet as well as ganciclovir.

Acquired Immunodeficiency Syndrome↗

Inhibition of adenylyl and guanylyl cyclase isoforms by the antiviral drug foscarnet.

The pyrophosphate (PP(i)) analog foscarnet inhibits viral DNA-polymerases and is used to treat cytomegalovirus and human immunodeficiency vius infections. Nucleotide cyclases and DNA-polymerases catalyze analogous reactions, i.e. a phosphodiester bond formation, and have similar topologies in their active sites. Inhibition by foscarnet of adenylyl cyclase isoforms was therefore tested with (i) purified catalytic domains C1 and C2 of types I and VII (IC1 and VIIC1) and of type II (IIC2) and (ii) membrane-bound holoenzymes (from mammalian tissues and types I, II, and V heterologously expressed in Sf9 cell membranes). Foscarnet was more potent than PP(i) in suppressing forskolin-stimulated catalysis by both, IC1/IIC2 and VIIC1/IIC2. Stimulation of VIIC1/IIC2 by Galpha(s) relieved the inhibition by foscarnet but not that by PP(i). The IC(50) of foscarnet on membrane-bound adenylyl cyclases also depended on their mode of regulation. These findings predict that receptor-dependent cAMP formation is sensitive to inhibition by foscarnet in some, but not all, cells. This was verified with two cell lines; foscarnet blocked cAMP accumulation after A(2A)-adenosine receptor stimulation in PC12 but not in HEK-A(2A) cells. Foscarnet also inhibited soluble and, to a lesser extent, particulate guanylyl cylase. Thus, foscarnet interferes with the generation of cyclic nucleotides, an effect which may give rise to clinical side effects. The extent of inhibition varies with the enzyme isoform and with the regulatory input.

Adenylyl Cyclase Inhibitors↗

Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG protocol 093). AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

OBJECTIVE: To document response to foscarnet salvage therapy in patients with cytomegalovirus (CMV) retinitis who are intolerant of or resistant to ganciclovir. METHODS: Patients with AIDS and CMV retinitis who had documented hematologic intolerance or resistance to ganciclovir therapy received an induction course of foscarnet, 60 mg/kg every 8 h for 14 days, and subsequent chronic maintenance foscarnet therapy at a daily dose of 60, 90 or 120 mg/kg/day. The first 87 patients were randomly assigned to receive maintenance foscarnet at a dose of 60 or 90 mg/kg/day; all subsequent patients were assigned a maintenance dose of 120 mg/kg/day. RESULTS: A total of 156 evaluable patients were enrolled. Median time to retinitis progression and survival did not differ significantly among groups assigned to different maintenance foscarnet doses. Among patients with retinitis progression documented ophthalmologically occurring at < or = 2 week intervals, despite optimal doses of ganciclovir, time to progression on foscarnet therapy was a median 8 weeks at all doses studied. By dose assignment, there were no significant differences in serious drug-associated toxicity, although trends toward increased renal and hypocalcemic adverse events were observed at higher maintenance doses. CONCLUSION: In patients intolerant of ganciclovir, salvage foscarnet therapy resulted in a longer time to retinitis progression than reported previously in historic controls who terminated ganciclovir therapy. In patients who exhibited clinical resistance to ganciclovir, foscarnet appeared to have efficacy in controlling retinitis. No significant differences in either efficacy or toxicity were observed in the range of foscarnet maintenance doses studied.

AIDS-Related Opportunistic Infections↗

A double-blind placebo-controlled crossover trial of intravenous magnesium sulfate for foscarnet-induced ionized hypocalcemia and hypomagnesemia in patients with AIDS and cytomegalovirus infection.

Foscarnet (trisodium phosphonoformate hexahydrate) is an antiviral agent used to treat cytomegalovirus disease in immunocompromised patients. One common side effect is acute ionized hypocalcemia and hypomagnesemia following intravenous administration. Foscarnet-induced ionized hypomagnesemia might contribute to ionized hypocalcemia by impairing excretion of preformed parathyroid hormone (PTH) or by producing target organ resistance. Prevention of ionized hypomagnesemia following foscarnet administration could blunt the development of ionized hypocalcemia. To determine whether intravenous magnesium ameliorates the decline in ionized calcium and/or magnesium following foscarnet infusions, MgSO(4) at doses of 1, 2, and 3 g was administered in a double-blind, placebo-controlled, randomized, crossover trial to 12 patients with AIDS and cytomegalovirus disease. Overall, increasing doses of MgSO(4) reduced or eliminated foscarnet-induced acute ionized hypomagnesemia. Supplementation, however, had no discernible effect on foscarnet-induced ionized hypocalcemia despite significant increases in serum PTH levels. No dose-related, clinically significant adverse events were found, suggesting that intravenous supplementation with up to 3 g of MgSO(4) was safe in this chronically ill population. Since parenteral MgSO(4) did not alter foscarnet-induced ionized hypocalcemia or symptoms associated with foscarnet, routine intravenous supplementation for patients with normal serum magnesium levels is not recommended during treatment with foscarnet.

AIDS-Related Opportunistic Infections↗

Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis.

The pyrophosphate analogue, foscarnet, selectively inhibits the DNA polymerase of human herpes viruses, including cytomegalovirus, and the reverse transcriptase of HIV. Viral replication is therefore prevented, but resumes when the drug is cleared from infected cells. In vitro, the combination of foscarnet and zidovudine (azidothymidine) has an additive effect against cytomegalovirus and acts synergistically against HIV. An improvement in cytomegalovirus retinitis is obtained in over 85% of affected AIDS patients during foscarnet induction therapy, but relapse usually occurs within a month of ceasing treatment. There is a similar duration of remission during maintenance therapy given for 5 days each week, but this can be extended 4- to 5-fold with daily administration of higher doses. In allograft recipients, progression of retinitis can be halted by foscarnet until immune function recovers and eradicates the virus. The incidence of acute renal failure, which is common during foscarnet therapy, may be reduced by dosage adjustment and adequate prehydration. Anaemia, phlebitis, nausea and vomiting, and disturbances in serum calcium and phosphate levels, perhaps resulting from uptake of foscarnet into bone or chelation with ionised calcium, have also been associated with administration of the drug. Cytomegalovirus retinitis is difficult to treat, with few therapeutic options available. Although treatment with foscarnet produces some severe adverse effects, with care these can be minimised, and the drug produces clinical improvement in a large proportion of patients; this is a highly encouraging finding at this stage in its development. Preliminary comparative data indicate that foscarnet and ganciclovir are similarly effective, but foscarnet may have some theoretical advantages in AIDS patients since it can be used in combination with zidovudine without potentiating myelosuppression.

Acquired Immunodeficiency Syndrome↗

Foscarnet in the treatment of cytomegalovirus infection of the esophagus and colon in patients with the acquired immune deficiency syndrome.

Foscarnet, administered via a central line, was used for the treatment of 18 episodes of cytomegalovirus (CMV) esophageal ulceration in 15 patients, and in the treatment of 27 episodes of CMV colitis in 22 patients. In 15 of the 18 episodes of the esophageal disease, there was complete loss of symptoms within 2 wk. Only three of the 15 patients responding to foscarnet therapy had a relapse of their esophageal disease. Two of these patients were successfully retreated with foscarnet. Of the 22 patients receiving foscarnet for CMV colitis, four died during foscarnet therapy. Of the 18 patients completing the course of treatment with foscarnet for first-episode CMV colitis, 11 remitted completely and six had a partial remission. All patients with partial remission had a second pathogen responsible for the continuation of their diarrhea. Only one patient completing a course of foscarnet failed to respond microscopically to treatment. Three patients experienced relapse of their CMV colitis, two of whom responded to further courses of foscarnet. Foscarnet is an effective therapy for CMV disease of the gastrointestinal tract, with rapid resolution of clinical symptoms, long-term remission of esophageal disease, and shorter disease-free periods for CMV colitis.

Acquired Immunodeficiency Syndrome↗

Relationship between foscarnet exposure, baseline cytomegalovirus (CMV) blood culture and the time to progression of CMV retinitis in HIV-positive patients.

OBJECTIVE: To determine some of the factors influencing the time to progression of cytomegalovirus (CMV) retinitis among HIV-infected patients being treated with foscarnet. DESIGN: A retrospective analysis of two open-label Phase I/II studies in multiple university hospitals. Patients were studied in both inpatient and outpatient settings. PATIENTS: Of the patients in the databases examined, 31 had adequate pharmacokinetic information and 29 had information on outcome and the other patient covariates. INTERVENTION: After induction therapy with foscarnet at a dose of 60 mg/kg three times daily was completed, patients had maintenance therapy with 60-120 mg/kg foscarnet once daily. Doses were subsequently adjusted for changed estimated creatinine clearance. MEASUREMENTS: The measured endpoint was time to progression of CMV retinitis. The independent variables examined to determine influence on time to progression included mean peak foscarnet concentration, mean area under the concentration-time curve (AUC) for foscarnet, the positive or negative outcome of a baseline blood culture for CMV, the initial CD4 cell count for a patient and the peak CD4 cell count observed during maintenance therapy. RESULTS: A wide range (-10-fold) of foscarnet AUC was observed, even though only a fourfold dose range was employed, and doses were altered for changing estimated creatinine clearance. In a multivariate Cox model, only AUC and the status of the baseline CMV blood culture significantly affected the time to progression of the retinitis. CONCLUSION: The AUC produced by a dose of foscarnet has a wide interindividual range. The AUC of foscarnet significantly altered time to progression of the retinitis. However, patients with positive baseline CMV blood cultures had a significantly more shallow dose-response curve. This indicates that the added risk of nephrotoxicity which is present with aggressive foscarnet dosing might be best borne by the subgroup of patients with a positive CMV blood culture at baseline.

Analysis of Variance↗

Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group.

OBJECTIVES: To determine the best therapeutic regimen, using currently approved drugs, for treatment of relapsed cytomegalovirus (CMV) retinitis. DESIGN: Multicenter, randomized, controlled clinical trial. SETTING: Ophthalmology, and acquired immunodeficiency syndrome (AIDS) services at tertiary care medical centers. PATIENTS: Two hundred seventy-nine patients with AIDS and either persistently active or relapsed CMV retinitis. INTERVENTION: Patients were randomized to one of three therapeutic regimens: induction with foscarnet sodium at 90 mg/kg intravenously every 12 hours for 2 weeks, followed by maintenance at a dosage of 120 mg/kg per day (foscarnet group); induction with ganciclovir sodium at 5 mg/kg intravenously every 12 hours for 2 weeks followed by maintenance at 10 mg/kg per day (ganciclovir group); or continuation of previous maintenance therapy plus induction with the other drug (either ganciclovir or foscarnet) for 2 weeks followed by maintenance therapy with both drugs, ganciclovir sodium at 5 mg/kg per day and foscarnet sodium at 90 mg/kg per day (combination therapy group). OUTCOMES: Mortality, retinitis progression, visual acuity, visual fields, and morbidity. RESULTS: The mortality rate was similar among the three groups. Median survival times were as follows: foscarnet group, 8.4 months; ganciclovir group, 9.0 months; and combination therapy group, 8.6 months (P=.89). Comparison of retinitis progression, as evaluated in a masked fashion by the centralized Fundus Photograph Reading Center (FPRC), revealed that combination therapy was the most effective regimen for controlling the retinitis. The median times to retinitis progression were as follows: foscarnet group, 1.3 months; ganciclovir group, 2.0 months; and combination therapy group, 4.3 months (P<.001). Although no difference could be detected in visual acuity outcomes, visual field loss and retinal area involvement on fundus photographs both paralleled the progression results, with the most favorable results in the combination therapy group. The rates of visual field loss were as follows: foscarnet group, 28 degrees per month; ganciclovir group, 18 degrees per month; combination therapy group, 16 degrees per month (P=.009); and the rates of increase of retinal area involved by CMV were as follows: foscarnet group, 2.47% per month; ganciclovir group, 1.40% per month; and combination therapy group, 1.19% per month (P=.04). While side effects were similar among the three treatment groups, combination therapy was associated with the greatest negative impact of treatment on quality-of-life measures. CONCLUSION: For patients with AIDS and CMV retinitis whose retinitis has relapsed and who can tolerate both drugs, combination therapy appears to be the most effective therapy for controlling CMV retinitis.

AIDS-Related Opportunistic Infections↗

Is there a pharmacokinetic interaction between foscarnet and zalcitabine during concomitant administration?

Foscarnet, an antiviral agent used in the treatment of cytomegalovirus infection, and zalcitabine, an antiretroviral nucleoside analogue used in the treatment of human immunodeficiency virus infection, are commonly used concomitantly. Foscarnet and zalcitabine may interact pharmacokinetically, as both compounds are partially eliminated by renal tubular secretion. Owing to dose-related toxicities associated with these two drugs, it is essential that we have data regarding their pharmacokinetic disposition during concomitant therapy. Twelve patients randomly received either foscarnet (four doses) or zalcitabine (five doses) (Phase 1), followed by concomitant foscarnet (four doses) and zalcitabine (six doses) (Phase 2), followed by dosing with the drug not received in Phase 1 (Phase 3). Following the last dose in each phase of the study, serial plasma samples were collected over 8 hours for zalcitabine and over 12 hours for foscarnet to determine the pharmacokinetics of each drug using noncompartmental analysis. Foscarnet plasma and urine levels were determined using high-performance liquid chromatography, and zalcitabine levels were determined using radioimmunoassay. No clinically significant alterations in the pharmacokinetics of foscarnet or zalcitabine occurred in this study. Thus despite the potential for foscarnet and zalcitabine to compete for renal tubular secretion, no apparent pharmacokinetic interaction exists between these two drugs at the clinically relevant doses studied.

Administration, Oral↗

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

In a previous study, we showed that patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT) who had cytomegalovirus (CMV) antigenemia with more than 4 CMV antigen-positive cells/200,000 have a high transplant-related mortality (TRM) rate, despite treatment with ganciclovir or foscarnet. In an attempt to reduce TRM, 32 allogeneic HSCT recipients, between the ages of 16 and 55 years (median, 35 years), with CMV antigenemia (> or = 5 positive cells) developing at a median interval from HSCT of 49 days, were given combination treatment with foscarnet and ganciclovir for 15 days. The prescribed dose was 180 mg/kg/day of foscarnet and 10 mg/kg/day of ganciclovir: the median administered dose in the first 15 days, after adjusting for creatinine levels and peripheral blood counts, was 64% for foscarnet and 53% for ganciclovir. Maintenance was given with foscarnet and ganciclovir on alternate days for an additional 2 weeks. Thirty-one of 32 patients were on cyclosporine, 30 were on systemic antibiotics, and 9 were on intravenous amphotericin. Median laboratory values on days 1 and 15 of treatment were 1.0 and 1.1 mg/100 ml creatinine, 5.7 x 10(9)/L, and 4.1 x 10(9)/L white blood cells, and 78 x lO(9)/L and 72 x 10(9)/L platelets. All patients cleared CMV antigenemia by day +15, although CMV antigenemia recurred in 5 patients on maintenance therapy and in 14 patients off maintenance therapy: the dose of foscarnet (but not ganciclovir) received in the first 15 days was significantly lower in patients in whom antigenemia recurred within 30 days (P=0.0002). Six patients died, one with interstitial pneumonia, one with multiorgan failure, and four with infections. Twenty-six patients survived 119-1051 days after transplant. The actuarial TRM rate at 1 year is 23%. Eighteen patients who had received unmanipulated bone marrow transplants from HLA-identical siblings were compared with 15 matched controls who had been treated with a single drug (either foscarnet or ganciclovir) for CMV antigenemia (> or = 5 cells): the actuarial 1 year TRM rate was 13% for patients receiving combined treatment, compared with 47% for controls receiving a single drug (P=0.02). This study shows that combined foscarnet-ganciclovir is one therapeutic option for allogeneic HSCT recipients who develop CMV antigenemia with a high number of CMV antigen-positive cells. Treatment can be given together with cyclosporine and antibiotics with appropriate dose reductions. It produces prompt clearing of CMV infection, and may reduce TRM rates in comparison to single-agent therapy.

Adolescent↗