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PubMed1993

Foscarnet penetrates the blood-brain barrier: rationale for therapy of cytomegalovirus encephalitis.

Foscarnet (phosphonoformate) is a potent virustatic drug against herpes-like viruses and is widely used in the therapy of cytomegalovirus infections in immunosuppressed patients. To obtain data on its penetration across the blood-brain barrier, we determined concentrations of foscarnet in cerebrospinal fluid and in plasma specimens from 26 patients with human immunodeficiency virus (stages 2 to 6 by Walter Reed Army Institute of Research classification) after a single infusion of 90 mg of foscarnet per kg of body weight and at steady state by electrochemical detection by high-pressure liquid chromatography. Penetration coefficients were correlated with the integrity of the blood-brain barrier. After a single infusion of foscarnet, levels in plasma ranged from 297 to 1,775 micrograms/ml (990 to 5,920 mumol/liter), with a mean of 766 +/- 400 micrograms/ml. Corresponding levels in cerebrospinal fluid were 57 to 225 micrograms/ml (190 to 750 mumol/liter), with a mean of 131 +/- 52 micrograms/ml. The penetration coefficient was 0.05 to 0.72 (mean, 0.23 +/- 0.16). At steady state, mean foscarnet levels in plasma were 464 +/- 219 micrograms/ml (1,553 mumol/liter) and mean levels in cerebrospinal fluid were 308 +/- 155 micrograms/ml (1,023 mumol/liter). The penetration coefficient was 0.66 +/- 0.11. Although penetration coefficients were highly variable after a single administration and at steady state, the concentrations of foscarnet attained in cerebrospinal fluid are sufficient for complete inhibition of cytomegalovirus replication in vitro. In conclusion, we show that foscarnet seems to be the drug of choice for the treatment of cytomegalovirus encephalitis, because it penetrates the blood-brain barrier and is found in the cerebrospinal fluid in virustatic concentrations. Foscarnet might be considered for additive therapy for human immunodeficiency virus encephalitis in combination with zidovudine or dideoxyinosine.

AIDS-Related Opportunistic Infections↗

PubMed1993

Penetration of foscarnet into cerebrospinal fluid of AIDS patients.

The diffusion of foscarnet into cerebrospinal fluid (CSF) was studied in 27 patients with AIDS. Foscarnet was administered intravenously at various dosages at 12-h intervals. Concentrations in plasma and CSF at the end of foscarnet infusion or 1, 3, 5, 6, and 12 h after infusion were determined by high-performance liquid chromatography. Thirty-seven samples were obtained. The median concentration of foscarnet in CSF was 80 mumol/liter (range, 0 to 500 mumol/liter). The CSF foscarnet concentration was greater than the 50% inhibitory concentration for human immunodeficiency virus type 1 and was equal to or greater than the 50% inhibitory concentration for cytomegalovirus in most cases. The penetration of foscarnet into CSF, as expressed by the ratio of the concentration in CSF to the simultaneous concentration in plasma, ranged from 0 to 3.4 (median, 0.27) and was highly correlated with the presence of cells within CSF and the length of foscarnet therapy. Good diffusion of foscarnet in CSF allows evaluation of this drug in central nervous system cytomegalovirus and human immunodeficiency virus infections in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Effect of foscarnet on quantities of cytomegalovirus and human immunodeficiency virus in blood of persons with AIDS.

Four intravenous dosages of foscarnet given for 10 days were compared with no therapy in persons with AIDS who had asymptomatic cytomegalovirus (CMV) viremia. CMV viremia was quantitated by endpoint cell dilution microcultures, pp65 antigenemia assay, and measurement of CMV DNA in peripheral blood leukocytes by a quantitative-competitive PCR. Human immunodeficiency virus type 1 (HIV-1) viremia was quantitated by endpoint cell dilution microculture, serum p24 antigen assay, and PCR for HIV-1 RNA in plasma. Twenty-seven subjects who had received a median of 22 months of nucleoside antiretroviral therapy were enrolled. Twenty-two subjects received foscarnet, which was well tolerated and decreased the CMV burden, as reflected by all three indicator assays. During the 10 days of dosing, the level of CMV viremia, as measured by 50 percent tissue culture infective doses, decreased from 117.5 to 12.7 (P = 0.001), the amount of CMV DNA decreased from 20,328 copies to 622 copies per 150,000 leukocytes (P = 0.02), and the level of CMV pp65 antigenemia decreased from 14.9 to 1.6 positive peripheral blood mononuclear cells per 50,000 leukocytes (P = 0.008). A significant pharmacodynamic relationship was found between the peak foscarnet concentration and a decrease in the level of CMV antigenemia (P < 0.05). Foscarnet had no effect on quantitative HIV-1 microcultures during the 10 days of treatment, but the HIV-1 p24 antigen level in serum decreased significantly, from 454 to 305 pg/ml (P = 0.01). Also, a significant pharmacodynamic relationship was seen between plasma HIV-1 RNA concentrations and both peak foscarnet concentration (P < 0.01) and the area under the foscarnet time-concentration curve (P < 0.05). Reductions in the levels of CMV and HIV-1 viremia correlated quantitatively with systemic exposure to foscarnet, whereas control subjects actually experienced an increase in CMV and HIV-1 burdens. The dual antiviral activity of foscarnet shown in this trial encourages investigation of its use in combination with other antiretroviral therapies for persons with AIDS.

AIDS-Related Opportunistic Infections↗

PubMed1999

Neoglycolipid conjugates of foscarnet with enhanced antiviral activity in cells infected with human cytomegalovirus and herpes simplex virus type 1.

The synthesis of a series of neoglycolipid conjugates of foscarnet as potential drug targeting forms or lipophilic prodrugs of foscarnet is described. The compounds were obtained from suitably protected neoglycolipids, in which the lipid chain consisted of 12 to 20 carbon atoms, by ethoxycarbonylphosphonylation at the 6-hydroxyl or 4-hydroxyl group followed by deprotection. The in vitro antiviral activity of the compounds was determined in human foetal lung cells infected with human cytomegalovirus (HCMV) or herpes simplex virus type 1 (HSV-1). Compounds in which the lipid chain consisted of 14 to 20 carbon atoms showed pronounced antiviral activity against HCMV and HSV-1, the highest activity being shown by trans-9-octadecen-1-yl 6-O-carboxyphosphonyl-alpha-D-glucopyranoside against HCMV (approximately 50 times that of foscarnet) and by eicosyl 6-O-carboxyphosphonyl-beta-D-galactopyranoside against HSV-1 (approximately 15 times that of foscarnet). Cytotoxicity was determined by assessing the capability of mitochondrial enzymes to metabolise MTT and gave TC50 values for the compounds that were 30 to 350 times higher than their IC50 values against HCMV and 5 to 15 times higher than their IC50 values against HSV-1. Foscarnet was not liberated on incubation of n-tetradecyl 6-O-carboxyphosphonyl-alpha-D-glucopyranoside with rat liver or intestine homogenate, neither could the neoglycolipid conjugate nor foscarnet be detected in rat plasma following oral administration. Further metabolic and pharmacokinetic studies are required in order to determine whether neoglycolipid conjugates of foscarnet can find a use as drug targeting forms of foscarnet.

Animals↗

PubMedDate not supplied

Concurrent use of foscarnet and ciprofloxacin may increase the propensity for seizures.

OBJECTIVE: To report a possible interaction between foscarnet and ciprofloxacin in two patients with AIDS, cytomegalovirus (CMV) retinitis, and disseminated Mycobacterium avium complex (MAC) infection and to review the available literature related to foscarnet-associated seizures. DATA SOURCE: Case report information was obtained from Medical Service Daily Rounds during the patients' hospitalization and from the patients' medical records. Computerized (MEDLINE) and manual (Index Medicus) search methods were used to obtain English-language literature published between 1980 and 1993. DATA SYNTHESIS: Foscarnet is a synthetic antiviral agent with activity against herpesviruses and HIV. The incidence of seizures with foscarnet infusion is high, ranging from 13 to 15 percent. Predisposing factors such as renal impairment, electrolyte and metabolic abnormalities, and underlying neurologic disorders have been associated with seizures during foscarnet therapy. We describe two patients with AIDS who developed generalized tonic-clonic seizures while receiving foscarnet and ciprofloxacin for the treatment of CMV retinitis and disseminated MAC infection, respectively. Neither of the patients had any of the aforementioned risk factors for foscarnet-associated seizures. CONCLUSIONS: Concurrent administration of ciprofloxacin, a known epileptogenic agent, and foscarnet may predispose patients to the development of seizures.

AIDS-Related Opportunistic Infections↗

PubMed1996

Disposition of foscarnet during peritoneal dialysis.

OBJECTIVE: To report the disposition of foscarnet in a patient undergoing peritoneal dialysis. CASE SUMMARY: A 34-year-old man with AIDS received foscarnet for the treatment of esophageal cytomegalovirus. We characterized the clearance of foscarnet in this patient during continuous cyclic peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD). DISCUSSION: The foscarnet half-lives during CCPD and CAPD were 41.4 and 45.8 hours, respectively. These values are significantly greater than the half-life of 4.5 hours observed in patients with normal renal function and about half that reported in anuric patients undergoing hemodialysis during the interdialytic period. The CCPD and CAPD clearances of foscarnet were 5.8 and 4.5 mL/min, respectively; the CAPD clearances of creatinine and urea nitrogen were 4.1 and 6.0 mL/min, respectively. The patient's estimated total body clearance values of foscarnet during CCPD and CAPD were 9.8 and 8.8 mL/min, respectively. Thus, CCPD and CAPD augmented the patient's residual clearance of foscarnet by 145% and 105%, respectively. CONCLUSIONS: Since incremental increases in residual clearance of 30% or more generally will result in clinically significant changes in a drug's serum concentration, foscarnet dosage needs to be individualized for patients receiving peritoneal dialysis.

Acute Kidney Injury↗

PubMed2002

Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation.

The present study compared foscarnet with ganciclovir for preemptive therapy of cytomegalovirus (CMV) infection after allogeneic blood or marrow stem cell transplantation (SCT). Patients with CMV infection, as detected by weekly antigenemia or polymerase chain reaction (PCR) in blood leukocytes, were randomized to intravenous therapy for 2 weeks with either foscarnet at 60 mg/kg or ganciclovir at 5 mg/kg administered every 12 hours; if CMV infection remained detectable, patients received an additional 2 weeks of intravenous foscarnet at 90 mg/kg or ganciclovir at 6 mg/kg given once daily for 5 days per week, after which therapy was stopped. Primary efficacy endpoint was the occurrence of CMV disease or death from any cause within 180 days after SCT. A total of 213 patients were treated with either foscarnet (n = 110) or ganciclovir (n = 103). Kaplan-Meier estimates of event-free survival within 180 days after SCT were similar in the 2 treatment groups (P =.6). During study treatment, severe neutropenia (< 0.5 x 10(9)/L) occurred in 11 (11%) patients on ganciclovir versus 4 (4%) patients on foscarnet (P =.04), and impaired renal function was observed in 5 (5%) patients on foscarnet versus 2 (2%) patients on ganciclovir (P =.4). Neutropenia or thrombocytopenia required discontinuation of ganciclovir in 6 (6%) patients but in no foscarnet-treated patient (P =.03). After allogeneic SCT, preemptive therapy of CMV infection with foscarnet shows similar efficacy as with ganciclovir, but is associated with a lower proportion of patients who develop severe neutropenia and who require discontinuation of antiviral therapy due to hematotoxicity.

Adolescent↗

PubMed1992

Review of the toxicities of foscarnet.

The primary dose-limiting adverse effects associated with foscarnet treatment of cytomegalovirus retinitis in patients with AIDS are renal impairment and ionized hypocalcemia. Dose-limiting renal impairment, consisting of significant alterations in serum creatinine levels or creatinine clearance or acute renal failure, has been observed in 10-20% of AIDS patients receiving foscarnet via intermittent i.v. infusion. Nephrotoxicity can be minimized by adjusting dosage according to creatinine clearance and by ensuring that adequate hydration is provided throughout foscarnet therapy. Transient decreases in serum or plasma ionized calcium levels appear to occur in all patients during foscarnet infusion, with these decreases being observed in the absence of changes in total calcium levels. Hypocalcemia produces mild symptoms in some patients and may play a role in unexplained cases of arrhythmia or seizure. Careful attention should be given to levels of total calcium and other minerals during foscarnet treatment, and the occurrence of symptomatic hypocalcemia should prompt evaluation of ionized calcium concentrations and foscarnet dose reduction. Another potentially treatment-limiting effect attributed to foscarnet is penile ulceration, which appears to result from exposure of the glans penis to unchanged foscarnet in the urine.

Antiviral Agents↗

PubMed1986

Sensitivity of cytomegalovirus to intravenous foscarnet treatment.

Intravenous foscarnet was given on an emergency basis to 30 immunosuppressed patients with cytomegalovirus (CMV) disease, of whom 28 were organ transplant recipients. Thirteen patients responded to foscarnet by cessation of CMV secretion. The in vitro sensitivity to foscarnet of the CMV isolates from non-responders before, during and after foscarnet treatment was similar to that of viral isolates from responders before or during foscarnet treatment and also to CMV isolates from non-treated patients, with mean in vitro IC50 values of 239-294 microM of foscarnet. Thus, there was no evidence of increased resistance of the CMV isolates obtained after foscarnet treatment. A higher total foscarnet dose appeared to favor response.

Antiviral Agents↗

PubMed1994

Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial. 4. Visual outcomes. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group.

BACKGROUND: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immune deficiency syndrome (AIDS) and, untreated, is a blinding disorder. The Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial is a multicenter, randomized, controlled, unmasked, clinical trial that compared ganciclovir and foscarnet as treatments for CMV retinitis in patients with AIDS. METHODS: Patients with previously untreated CMV retinitis who enrolled in this trial were assigned randomly to treatment with either foscarnet or ganciclovir and followed at regular intervals for visual outcomes, including progression of the retinitis, visual acuity, and visual fields. In October 1991, the treatment protocol was suspended due to a greater mortality in the ganciclovir-assigned group. RESULTS: The efficacy of the two drugs in controlling the CMV retinitis as measured by the time to first progression was similar. The relative risk for progression of the retinitis was 0.97 (ganciclovir versus foscarnet; P = 0.833), and the median time to first progression was 53 days in the foscarnet-assigned patients compared with 47 days in the ganciclovir-assigned patients (P = 0.997), as determined by a masked reading at a central fundus photograph reading center. By 120 days after randomization, progression was observed in 85% of patients in each treatment group. Visual acuity outcomes were similar for both groups; at 6 months after randomization, 88% of the foscarnet-assigned patients and 93% of the ganciclovir-assigned patients had a best-corrected visual acuity of 20/40 or better in the better eye (P = 0.325). Visual field scores were similar in the two groups; in all eyes affected with CMV retinitis, there was a mean 29 degrees/month loss of visual field in foscarnet-assigned patients compared with a 31 degrees/month loss in ganciclovir-assigned patients (P = 0.674). CONCLUSION: Although foscarnet was associated with a longer survival than ganciclovir, the two drugs appear equivalent in controlling CMV retinitis and preserving vision.

AIDS-Related Opportunistic Infections↗

PubMed1994

Toxicologic and pharmacokinetic analysis of intravitreal injections of foscarnet, either alone or in combination with ganciclovir.

PURPOSE: The retinal toxicity of single and repeated intravitreal injections of foscarnet was investigated. In addition, the effects of a combination of foscarnet and ganciclovir were studied, and a pharmacokinetic study to determine the ocular pharmacokinetics of foscarnet after intravitreal injection was carried out. METHODS: Forty rabbits (both albino and pigmented) were used in this study. The electroretinographic (ERG) a-waves and b-waves and oscillatory potentials (OP) were used as as indicators of retinal toxicity. Potential toxicity was also assessed by ophthalmoscopy and histologic studies (light and electron microscopy). RESULTS: The a-wave and b-wave were not deteriorated with 2.4 mg foscarnet after single or repeated injections. The OP remained unchanged. There was no ERG change after intravitreal injection of a combination of both drugs. No evidence of retinal toxicity was observed by indirect ophthalmoscopy in any case. Light and electron microscopy on semithin sections of retina failed to demonstrate any adverse effects, and showed normal organization and cytoarchitecture of all the layers of the retina without evidence of cytopathology. The ocular pharmacokinetics of foscarnet determined by noncompartmental analysis showed a 34-hour terminal elimination half-life and an apparent volume of distribution of 1.9 ml. CONCLUSIONS: Based on these results, high doses of foscarnet were not judged toxic to the rabbit retina, with single or repeated injections. Moreover, concomitant injection of the two drugs did not induce any retinal toxicity. These findings suggest that when systemic treatment is to be stopped in patients with AIDS for toxic side effects, either ganciclovir or foscarnet may be used intravitreally as an alternative. Because a combination of the two drugs has been shown to be synergistic, both ganciclovir and foscarnet might be simultaneously injected into the vitreous cavity to block progression of cytomegalovirus retinitis.

Animals↗

PubMed1997

Comparison of pharmacokinetics and dynamics of two dosage regimens of foscarnet in AIDS patients with Cytomegalovirus retinitis.

OBJECTIVE: To compare the pharmacokinetics of foscarnet administered as an infusion twice daily (BID) or thrice daily (TID), and to compare the effects on the electrolyte balance, cardiac and renal functions over a 3-week induction treatment of Cytomegalovirus (CMV) retinitis. METHODS: Pharmacokinetics/dynamics of foscarnet were investigated on treatment days 1, 14 and 21. Twelve AIDS patients with CMV retinitis completed the investigation period. Concentrations of foscarnet and electrolytes were assayed by high-performance liquid chromatography (HPLC) and by an ion-selective analyser, respectively. RESULTS: The pharmacokinetics of the two regimens were essentially similar. Foscarnet plasma and creatinine clearances were 2.0 and 1.6 ml.min-1.kg-1, respectively, in the BID group at steady state (day 21). In the TID group the corresponding values were 1.8 and 1.7 ml.min-1.kg-1, respectively. In both regimens the elimination half-life of foscarnet was 2-3 h. Ionized calcium concentrations were transiently decreased and strongly inversely correlated to foscarnet plasma concentrations in both regimens with no significant differences between groups. A trend towards prolongation of the QTc interval was seen when data from both treatments were analysed together. CONCLUSION: Our data suggest comparable pharmacokinetics of foscarnet after intermittent administration BID or TID during a 3-week induction period.

AIDS-Related Opportunistic Infections↗

PubMed2000

Foscarnet--an alternative for cytomegalovirus prophylaxis after allogeneic stem cell transplantation?

Cytomegalovirus (CMV) disease is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT) and is associated with high morbidity and mortality. Early detection of the disease by antigenemia testing and polymerase chain reaction (PCR) along with pre-emptive antiviral therapy has been shown to be very effective in decreasing the incidence of CMV. We performed an uncontrolled observational study in 21 patients after HSCT (14 related, 7 unrelated donors) to evaluate the efficacy and toxicity of foscarnet administered as prophylaxis for CMV reactivation. Ten patients received bone marrow, and eleven patients received peripheral blood stem cells. All patients received foscarnet prophylaxis to study side effects, incidence of CMV reactivation, CMV disease, and transplant-related mortality. Foscarnet (90 mg/kg) was given every 12 h, day +11 to day +16. Thereafter, foscarnet (90 mg/kg) was given once per day, three times per week until day +60. The incidence of CMV reactivation detected by antigenemia (pp65 antigen) or PCR was 23.8% (5 of 21 patients). Two patients developed CMV disease and one patient died of CMV-pneumonia. Seventeen patients (81%) reported severe side effects, such as gastrointestinal disturbance, headache, and urethritis. In eight patients (38%), the dose of foscarnet had to be reduced and, in six patients (28.5%), foscarnet application was discontinued because of side effects. Compared with other groups, we believe that the potential benefit of foscarnet administration in this early setting is outweighed by the risks of severe toxicity.

Adult↗

PubMed1992

Design of a randomized controlled trial of foscarnet in patients with cytomegalovirus retinitis associated with acquired immunodeficiency syndrome.

In a controlled trial of foscarnet in the treatment of cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS), patients with non-immediately sight-threatening lesions were randomized to receive immediate treatment with foscarnet or foscarnet treatment delayed until the first signs of retinitis progression. Foscarnet induction therapy was administered at a dosage of 60 mg/kg 3 times/day via 1-hour intravenous infusion for 21 days. Foscarnet maintenance therapy was administered at a dosage of 90 mg/kg/day via 2-hour infusion. Foscarnet was well tolerated and effective in delaying progression of CMV retinitis in these patients. Final analysis of data from this study and data from other studies will help to determine what role foscarnet will have in the treatment of CMV retinitis in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS-related cytomegalovirus retinitis.

INTRODUCTION: The use of foscarnet and ganciclovir as a combination treatment for cytomegalovirus retinitis is increasing because of limitations associated with single agent therapy. METHODS: The pharmacokinetics of foscarnet and ganciclovir were determined in 13 patients receiving either concomitant therapy (regimen A) or daily alternating therapy (regimen B) for maintenance of cytomegalovirus disease. For regimen A, 60 mg/kg intravenous foscarnet and 3.75 mg/kg ganciclovir were sequentially administered daily; for regimen B, 120 mg/kg foscarnet and 6 mg/kg ganciclovir were administered on alternating days. For both regimens, serial blood sampling for pharmacokinetic analysis was performed for each drug alone (day 1 or 2) and after 2 weeks of combination therapy. Plasma samples for foscarnet and ganciclovir analysis were performed by means of high-performance liquid chromatography. Pharmacokinetic analysis was performed with noncompartmental methods. RESULTS: For regimen A, the plasma clearance (CL) of foscarnet did not change in the presence of ganciclovir, averaging 0.12 +/- 0.08 and 0.11 +/- 0.02 L/hr/kg on study days 2 and 14, respectively (p = 0.34). The volume of distribution (VSS) and mean residence time (MRT) also did not change significantly. CL and MRT of foscarnet did not change for regimen B, although a slight increase in VSS was observed before (0.38 +/- 0.05 L/kg) and after (0.46 +/- 0.07 L/kg) alternating therapy (p = 0.03). Ganciclovir CL did not change for either regimen, with mean values of 0.21 +/- 0.10 and 0.25 +/- 0.10 L/hr/kg (regimen A, p = 0.17) and 0.32 +/- 0.10 and 0.34 +/- 0.11 L/hr/kg (regimen B, p = 0.24). MRT and VSS were also not significantly different. CONCLUSION: These plasma data suggest that further dosage adjustments are unnecessary for or alternating maintenance therapy.

AIDS-Related Opportunistic Infections↗

PubMed2005

Phenotypic characterisation of cytomegalovirus DNA polymerase: a method to study cytomegalovirus isolates resistant to foscarnet.

A phenotypic method was developed to test mutations in the human cytomegalovirus (HCMV) DNA polymerase gene (UL54) suspected to confer resistance to foscarnet. This method was used to determine the biochemical phenotype of wild-type and mutated HCMV DNA polymerases that had been synthesised in vitro as follows. The UL54 genes were amplified from foscarnet-resistant and -sensitive isolates by PCR and the products were cloned into an expression vector under the control of a T7 promoter. Mutations were introduced by site-directed mutagenesis into wild-type gene UL54 and then polymerases were synthesised by using a commercially available coupled transcription/translation system. Polymerase activity was measured with and without foscarnet by detecting the incorporation of digoxigenin-labelled nucleotides into the growing DNA chain. The results of this non-radioactive assay were consistent with those obtained with the conventional radioactive assay. It was found that the activity of polymerases containing the V715M or E756K mutations was inhibited by foscarnet at concentrations 70- and 30-fold higher than that of wild-type polymerase, respectively. Change N495K and a combination of changes K415R and S291P, both observed in foscarnet-resistant isolates, induced a 5- and 10-fold decrease in susceptibility to foscarnet, respectively. This non-radioactive phenotypic assay could be useful for the characterisation of mutations that confer HCMV resistance to foscarnet.

Cytomegalovirus↗

PubMed1999

Characterization of the DNA polymerase and thymidine kinase genesof herpes simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed.

Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients in whom acyclovir and foscarnet therapy sequentially failed. The 6 postacyclovir (prefoscarnet) HSV isolates were resistant to acyclovir and susceptible to foscarnet. Of the 9 postfoscarnet isolates, 8 were foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both drugs. Acyclovir- or foscarnet-resistant isolates retained susceptibility to cidofovir. The acyclovir-resistant isolates contained single-base substitutions or frameshift mutations in G or C homopolymer nucleotide repeats of the thymidine kinase gene. In contrast, the foscarnet-resistant strains contained single-base substitutions in conserved (II, III, or VI) or, more rarely, nonconserved (between I and VII) regions of the DNA polymerase (pol) gene. The single isolate exhibiting resistance to acyclovir and foscarnet contained mutations in both genes. In this study of clinical HSV isolates, DNA pol mutations conferring foscarnet resistance were not associated with decreased acyclovir or cidofovir susceptibility.

AIDS-Related Opportunistic Infections↗

PubMed1992

Effect of foscarnet therapy on human immunodeficiency virus p24 antigen levels in AIDS patients with cytomegalovirus retinitis.

Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured in 22 AIDS patients who had detectable serum antigen at baseline after induction and maintenance therapy of foscarnet for cytomegalovirus retinitis in phase I/II multicenter trials. The HIV p24 antigen levels decreased from a baseline value of 199 +/- 236 (mean +/- SD) and 140 pg/mL (median) to 106 +/- 218 and 28 pg/mL after 14 days of foscarnet induction therapy (60 mg/kg every 8 h). During chronic foscarnet maintenance, there was a sustained decrease in mean HIV p24 antigen levels below pre-foscarnet therapy baseline concentrations for a median of 16 weeks after foscarnet induction. These results provide evidence for a sustained clinical antiretroviral effect of chronic foscarnet maintenance therapy, consistent with a recent report that foscarnet-treated AIDS patients live longer than ganciclovir-treated patients.

Acquired Immunodeficiency Syndrome↗