NIH guideline for people with HIV: preferred therapy and its rating

“Treatment failure due to acyclovir resistance should be suspected if lesions do not begin to resolve within 7–10 days after initiation of anti-HSV therapy.” (opens the source at this quote in a new tab)
“Treatment of acyclovir-resistant HSV should be given in consultation with an infectious disease expert (AIII).” (opens the source at this quote in a new tab)
“IV foscarnet 40 mg/kg every 8–12 hours until clinical response (AI)” (opens the source at this quote in a new tab)
“Based on clinical response; typically 21–28 days or longer” (opens the source at this quote in a new tab)
“Therefore, the treatment of choice for acyclovir-resistant HSV is IV foscarnet (AI).” (opens the source at this quote in a new tab)

NIH guideline for people with HIV: specialist consultation and laboratory monitoring during foscarnet

“Systemic foscarnet and cidofovir are nephrotoxic medications; treatment should be given in consultation with an infectious diseases specialist (AIII) and with frequent laboratory monitoring (see Table 5).” (opens the source at this quote in a new tab)
“However, for people receiving IV acyclovir, cidofovir, or foscarnet, monitoring of renal function and dose adjustment as necessary is recommended at initiation of treatment and at least once or twice weekly for the duration of treatment, if stable” (opens the source at this quote in a new tab)

CDC sexually transmitted infections guideline: treatment of choice for acyclovir-resistant genital herpes

“If lesions persist or recur in a patient receiving antiviral treatment, acyclovir resistance should be suspected and a viral culture obtained for phenotypic sensitivity testing” (opens the source at this quote in a new tab)
“Such persons should be managed in consultation with an infectious disease specialist, and alternative therapy should be administered.” (opens the source at this quote in a new tab)
“Foscarnet (40–80 mg/kg body weight IV every 8 hours until clinical resolution is attained) is the treatment of choice for acyclovir-resistant genital herpes” (opens the source at this quote in a new tab)
“Foscarnet and cidofovir are nephrotoxic medications that require intensive laboratory monitoring and infectious disease specialist consultation.” (opens the source at this quote in a new tab)

Hematopoietic cell transplantation guideline: treatment of choice for resistant disease

“Acyclovir-resistant HSV infection occurs mainly in the setting of low-dose prophylaxis, intermittent treatment, or with HSV-seronegative donors” (opens the source at this quote in a new tab)
“Foscarnet is the treatment of choice for resistant disease (BI); cidofovir may serve as an alternative (CIII).” (opens the source at this quote in a new tab)
“Because of its substantial renal and infusion-related toxicity, foscarnet is not recommended for routine HSV prophylaxis among HCT recipients (DIII).” (opens the source at this quote in a new tab)

European Conference on Infections in Leukemia: regimen for resistance to acyclovir or famciclovir

“Acyclovir-resistant HSV isolates are usually susceptible to antiviral agents, such as foscarnet and cidofovir, that do not require viral thymidinie kinase for activation (III).” (opens the source at this quote in a new tab)
“In several cases, multidrug-resistant HSV strains causing disease have been documented (III).” (opens the source at this quote in a new tab)
“If HSV disease is unresponsive to antiviral therapy given at maximum dose, resistance testing should be performed (CIII).” (opens the source at this quote in a new tab)
“Foscarnet 60 mg/kg q12h iv or 40 mg/kg q8h iv for 7-21 d or until complete healing (BIII)” (opens the source at this quote in a new tab)

American Society of Transplantation guideline for solid organ transplant recipients

“Acyclovir-resistant HSV is less common in SOT patients than in HSCT and can be treated with foscarnet, though other novel therapies are currently under investigation.” (opens the source at this quote in a new tab)

British Association for Sexual Health and HIV guideline: systemic therapy for drug-resistant herpes

“TK-deficient strains are susceptible to foscarnet and cidofovir which do not depend upon TK but which inhibit viral DNA polymerase.” (opens the source at this quote in a new tab)
“Systemic therapy with either foscarnet or cidofovir is generally preferred to treat drug resistant herpes in those living with HIV.” (opens the source at this quote in a new tab)
“There is evidence for foscarnet 40 mg/kg body weight IV every 8 h (I, A)” (opens the source at this quote in a new tab)

European guideline for genital herpes: systemic therapy for drug-resistant herpes

“Although rare in immunocompetent individuals, clinically refractory lesions due to genital HSV are a major problem in patients with severe immunodeficiency, including late‐stage HIV.” (opens the source at this quote in a new tab)
“Systemic therapy with either foscarnet or cidofovir is generally preferred to treat drug‐resistant herpes in those living with HIV.” (opens the source at this quote in a new tab)
“The efficacy, safety and durability of the therapeutic response of these agents have yet to be determined in prospective controlled trials.” (opens the source at this quote in a new tab)

Position in guidelines as summarized in a review of transplant recipients

“i.v. FOS is the recommended alternative therapy for HSV resistant to nucleoside analogues.” (opens the source at this quote in a new tab)
“FOS is the only FDA-approved medication for R/R HSV infections to date.” (opens the source at this quote in a new tab)

Foscarnet regimen, monitoring, and regulatory status as tabulated in a review

Field	Quoted entry
Dose	“80–120 mg/kg/day i.v. in 2–3 divided doses.”“i.v. hydration with each dose.”
Clinically significant adverse reactions	“GI toxicity: nausea, vomiting, diarrhoea.”“Nephrotoxicity: renal insufficiency”“Electrolyte imbalances: hypokalaemia, hypocalcaemia, hypomagnesaemia, hypophosphataemia.”
Monitoring	“Serum creatinine”“Electrolytes”“Electrocardiogram”“Signs of volume overload”
FDA approval or off-label use	“FDA-approved”

Labeled indication for acyclovir-resistant mucocutaneous HSV infection

“FOSCAVIR is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients.” (opens the source at this quote in a new tab)
“SAFETY AND EFFICACY OF FOSCAVIR HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER HSV INFECTIONS (e.g., RETINITIS, ENCEPHALITIS); CONGENITAL OR NEONATAL HSV DISEASE; OR HSV IN NONIMMUNOCOMPROMISED INDIVIDUALS.” (opens the source at this quote in a new tab)

Labeled dose and duration for acyclovir-resistant HSV infection

“For acyclovir-resistant HSV patients, 40 mg/kg (minimum one hour infusion) either every 8 or 12 hours for 2-3 weeks or until healed.” (opens the source at this quote in a new tab)
“THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATES SHOULD NOT BE EXCEEDED. ALL DOSES MUST BE INDIVIDUALIZED FOR PATIENTS’ RENAL FUNCTION.” (opens the source at this quote in a new tab)

Labeled administration: controlled infusion through an infusion pump

“CAUTION - DO NOT ADMINISTER FOSCAVIR BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF FOSCAVIR MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS. CARE SHOULD BE TAKEN TO AVOID UNINTENTIONAL OVERDOSE BY CAREFULLY CONTROLLING THE RATE OF INFUSION. THEREFORE, AN INFUSION PUMP MUST BE USED. IN SPITE OF THE USE OF AN INFUSION PUMP, OVERDOSES HAVE OCCURRED.” (opens the source at this quote in a new tab)
“FOSCAVIR is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein. The rate of infusion must be no more than 1 mg/kg/minute.” (opens the source at this quote in a new tab)
“The standard 24 mg/mL solution may be used with or without dilution when using a central venous catheter for infusion.” (opens the source at this quote in a new tab)
“When a peripheral vein catheter is used, the 24 mg/mL injection must be diluted to a 12 mg/mL concentration with 5% dextrose in water or with a normal saline solution prior to administration to avoid local irritation of peripheral veins.” (opens the source at this quote in a new tab)

Labeled hydration with each infusion

“Hydration may reduce the risk of nephrotoxicity. It is recommended that 750–1000 mL of normal saline or 5% dextrose solution should be given prior to the first infusion of FOSCAVIR to establish diuresis. With subsequent infusions, 750–1000 mL of hydration fluid should be given with 90–120 mg/kg of FOSCAVIR, and 500 mL with 40–60 mg/kg of FOSCAVIR. Hydration fluid may need to be decreased if clinically warranted. After the first dose, the hydration fluid should be administered concurrently with each infusion of FOSCAVIR.” (opens the source at this quote in a new tab)
“Adequate hydration is recommended to establish a diuresis (see Hydration for recommendation), both prior to and during treatment to minimize renal toxicity (see WARNINGS), provided there are no clinical contraindications.” (opens the source at this quote in a new tab)

Labeled dose adjustment by creatinine clearance: rules

“FOSCAVIR dosing must be individualized according to the patient’s renal function status. Refer to Table 13 below for recommended doses and adjust the dose as indicated. Even patients with serum creatinine in the normal range may require dose adjustment; therefore, the dose should be calculated at baseline and frequently thereafter.” (opens the source at this quote in a new tab)
“To reduce the risk of nephrotoxicity, creatinine clearance (mL/min/kg) should be calculated even if serum creatinine is within the normal range, and doses should be adjusted accordingly.” (opens the source at this quote in a new tab)
“During FOSCAVIR therapy if creatinine clearance falls below the limits of the dosing nomograms (0.4 mL/min/kg), FOSCAVIR should be discontinued, the patient hydrated, and monitored daily until resolution of renal impairment is ensured.” (opens the source at this quote in a new tab)
“FOSCAVIR is not recommended in patients undergoing hemodialysis because dosage guidelines have not been established.” (opens the source at this quote in a new tab)
“Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances <50 mL/min are limited.” (opens the source at this quote in a new tab)

Labeled dose adjustment by creatinine clearance: induction doses for HSV infection

Creatinine clearance (mL/min/kg)	Dose (mg/kg) equivalent to 80 mg/kg/day total (40 mg/kg every 12 hours)	Dose (mg/kg) equivalent to 120 mg/kg/day total (40 mg/kg every 8 hours)
Greater than 1.4	“40 Q12h”	“40 Q8h”
Greater than 1.0 to 1.4	“30 Q12h”	“30 Q8h”
Greater than 0.8 to 1.0	“20 Q12h”	“35 Q12h”
Greater than 0.6 to 0.8	“35 Q24h”	“25 Q12h”
Greater than 0.5 to 0.6	“25 Q24h”	“40 Q24h”
Greater than 0.4 to 0.5	“20 Q24h”	“35 Q24h”
Less than 0.4	“Not recommended”	“Not recommended”

Randomized trial against vidarabine in AIDS: design as reported in the published abstract

“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.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine.” (opens the source at this quote in a new tab)

Randomized trial against vidarabine in AIDS: healing, pain, and viral shedding as reported in the published abstract

“The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy.” (opens the source at this quote in a new tab)
“In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)

Randomized trial against vidarabine in AIDS: toxicity and relapse after treatment

“Three patients had new neurologic abnormalities while receiving vidarabine.” (opens the source at this quote in a new tab)
“No patient discontinued foscarnet because of toxicity.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)
“For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine.” (opens the source at this quote in a new tab)

Controlled trial against vidarabine as described in the prescribing information

“In a controlled trial, patients with AIDS and mucocutaneous, acyclovir-resistant HSV infection were randomized to either FOSCAVIR (N=8) at a dose of 40 mg/kg TID or vidarabine (N=6) at a dose of 15 mg/kg per day.” (opens the source at this quote in a new tab)
“Eleven patients were nonrandomly assigned to receive treatment with FOSCAVIR because of prior intolerance to vidarabine.” (opens the source at this quote in a new tab)
“Lesions in the eight patients randomized to FOSCAVIR healed after 11 to 25 days; seven of the 11 patients nonrandomly treated with FOSCAVIR healed their lesions in 10 to 30 days.” (opens the source at this quote in a new tab)
“Vidarabine was discontinued because of intolerance (N=4) or poor therapeutic response (N=2).” (opens the source at this quote in a new tab)

Dose-comparison trial of twice-daily and three-times-daily dosing as described in the prescribing information

“In a second trial, forty AIDS patients and three bone marrow transplant recipients with mucocutaneous, acyclovir-resistant HSV infections were randomized to receive FOSCAVIR at a dose of either 40 mg/kg BID or 40 mg/kg TID.” (opens the source at this quote in a new tab)
“Fifteen of the 43 patients had healing of their lesions in 11 to 72 days with no difference in response between the two treatment groups.” (opens the source at this quote in a new tab)

Dose-comparison trial in AIDS: preliminary published report

“A recently completed dose-comparative trial of foscarnet in AIDS patients with acyclovir-resistant HSV has confirmed the safety and efficacy of two doses of foscarnet (40 mg/kg every 8 or 12 hours) in the treatment of this disease, as well as providing preliminary evidence supporting the utility of foscarnet maintenance therapy in delaying recurrence of HSV lesions.” (opens the source at this quote in a new tab)
“Analysis of data from this trial has been complicated by the tremendous variability in lesion size at initiation of therapy, making any statistically valid comparison of treatment regimens almost impossible.” (opens the source at this quote in a new tab)

Case series of 26 people with AIDS: response, viral shedding, and discontinuation

“Twenty-six consecutive patients are reported with human immunodeficiency virus infection, who received foscarnet therapy for acyclovir-resistant HSV.” (opens the source at this quote in a new tab)
“Clinical response was noted in 81% of patients; complete reepithelialization of HSV lesions occurred in 73%.” (opens the source at this quote in a new tab)
“Cessation of viral shedding was documented in all of the 11 patients who were recultured.” (opens the source at this quote in a new tab)
“Although adverse effects were frequent, in only 3 patients (12%) did toxicity necessitate discontinuation of therapy.” (opens the source at this quote in a new tab)

Uncontrolled trial in 4 people with AIDS and acyclovir-resistant HSV-2 infection

“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.” (opens the source at this quote in a new tab)
“Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days.” (opens the source at this quote in a new tab)
“All patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces.” (opens the source at this quote in a new tab)

Multicenter cohort of 31 foscarnet-treated episodes: design and population

“This was a multicenter retrospective study of adults treated with foscarnet for HSV infection between January 2012 and December 2017.” (opens the source at this quote in a new tab)
“Acyclovir-resistant HSV infection was defined based on genotypic or phenotypic testing results; refractory infection was defined as infection not improving after 5 days of treatment-dosed antiviral therapy in those not tested for resistance.” (opens the source at this quote in a new tab)
“Twenty-nine patients had 31 episodes of HSV (15/18 resistant; among episodes without resistance testing, 7/10 refractory; 3 not evaluable) treated with foscarnet.” (opens the source at this quote in a new tab)
“All patients were immunocompromised including 19 (66%) with hematologic malignancy and 9 (31%) with HIV.” (opens the source at this quote in a new tab)
“Among the 19 patients (66%) with hematologic malignancy, 16 had undergone allogeneic HCT and 1 had undergone autologous HCT.” (opens the source at this quote in a new tab)

Multicenter cohort of 31 foscarnet-treated episodes: treatment duration, healing, and recurrence

“Of the 31 episodes of HSV that were treated with foscarnet, 15 (48%) were reported to heal by the end of or after foscarnet therapy” (opens the source at this quote in a new tab)
“The median duration of foscarnet therapy was 16 days (range, 6–85 days).” (opens the source at this quote in a new tab)
“The median time to lesion healing was 38 days (range, 9–1088 days), which included healing even after foscarnet was stopped.” (opens the source at this quote in a new tab)
“Seven episodes (23%) healed within 28 days.” (opens the source at this quote in a new tab)
“Among the 16 episodes not reported as healing, 14 (45%) did not resolve after foscarnet therapy and information was not available after foscarnet therapy on 2 episodes.” (opens the source at this quote in a new tab)
“Among the 15 episodes that resolved, 8 (53%) of these recurred at a median of 229 days (range, 31–1030 days).” (opens the source at this quote in a new tab)
“Pain cessation was reported in 5 of 17 episodes at a median on 74 days.” (opens the source at this quote in a new tab)

Real-world cohort of 125 hematopoietic cell transplant recipients: design and use of foscarnet

“This multicenter, retrospective, observational study describes real-world treatment patterns and clinical outcomes of refractory mucocutaneous HSV infections in a cohort of 125 HCT recipients from 7 major HCT centers in the United States.” (opens the source at this quote in a new tab)
“First anti-HSV treatment was a NUC (standard or high dose) in 100 patients (80.0%) and foscarnet in 25 patients (20.0%).” (opens the source at this quote in a new tab)
“The most common second line therapy was foscarnet in 94 patients (75.0%).” (opens the source at this quote in a new tab)
“The median time from the treatment index dated to the start of the first course of foscarnet was 12 days (Q1, Q3: 0, 23).” (opens the source at this quote in a new tab)
“Ninety-four patients received foscarnet, 6 received IV cidofovir, and 21 received topical antivirals for a total of 109 foscarnet courses, 6 IV cidofovir courses, and 28 topical antiviral courses.” (opens the source at this quote in a new tab)
“The treatment duration was a mean (SD) of 21.8 (13.8), 20.3 (10.1), and 41.0 (37.5) days for foscarnet, IV cidofovir, and topical antivirals, respectively.” (opens the source at this quote in a new tab)

Real-world cohort of 125 hematopoietic cell transplant recipients: healing and recurrence across all treatments

“Sixty-nine patients (55.2%) achieved our primary endpoint of complete healing.” (opens the source at this quote in a new tab)
“Forty patients (32.0%) died on therapy and 16 patients (12.8%) were censored before healing.” (opens the source at this quote in a new tab)
“Complete healing was achieved at a median of 38 days (Q1, Q3: 26, 65; range: 257) from the treatment index date” (opens the source at this quote in a new tab)
“The cumulative incidence of healing was 16.2% at day 28, 31.2% at day 42, and 53.4% at day 90 from the treatment index date.” (opens the source at this quote in a new tab)
“At 1 year, 22 patients (31.9%) died and 27 patients (39.1%) had 1 or more recurrent HSV episode(s).” (opens the source at this quote in a new tab)

Real-world cohort of 125 hematopoietic cell transplant recipients: care setting for foscarnet

“Foscarnet requires daily IV administration; consequently, initiation of foscarnet may be deferred until the lesions worsen and/or hospitalization is deemed necessary based on physician judgment and patient preferences.” (opens the source at this quote in a new tab)
“Foscarnet was the most common second-line therapy, administered in a health care setting (hospital and/or hospital-associated infusion clinic) for a mean duration of 21.8 days.” (opens the source at this quote in a new tab)

Single-center cohort of 18 allogeneic transplant recipients: regimens and response

“We reviewed the medical records of patients with a microbiologic diagnosis of acyclovir-resistant HSV by plaque reduction test who received an HCT from 2002 through 2014.” (opens the source at this quote in a new tab)
“A total of 4028 HCTs were performed during the study period, and 18 of the recipients met the diagnostic criteria for acyclovir-resistant HSV.” (opens the source at this quote in a new tab)
“All patients were initially treated with high-dose oral valacyclovir (1000 mg every 8 hours) or intravenous acyclovir (5–10 mg/kg every 8 hours) without a response and then were transitioned to foscarnet and/or cidofovir (topical or intravenous).” (opens the source at this quote in a new tab)
“Foscarnet treatment dose used at 40 mg/kg/dose every 8 to 12 hours” (opens the source at this quote in a new tab)
“Five (28%) patients had a clinical response within two weeks of therapy, and 13 (72%) patients had slow or no clinical responses at 2 weeks (i.e., had no clinical improvement and/or had new lesions).” (opens the source at this quote in a new tab)
“Treatment with antiviral therapy was prolonged, reaching a median of 80 days in patients with good clinical responses and 100 days in patients with poor clinical responses.” (opens the source at this quote in a new tab)
“Combination antiviral strategies were used in most patients (n=12) and included intravenous foscarnet combined with topical therapy (either cidofovir 1% once daily or imiquimod) in five patients, intravenous foscarnet with topical acyclovir in two patients, and parenteral and topical cidofovir in two patients.” (opens the source at this quote in a new tab)
“Because of the common use of various combination strategies, we were unable to determine whether there was a difference in outcomes by treatment strategy.” (opens the source at this quote in a new tab)

Allogeneic transplant recipients in the United Kingdom: foscarnet in 8 participants with aciclovir-resistant HSV-1

“The prevalence of ACV-resistant HSV accounted for 17% (8/48) of infected HSV-1 cases.” (opens the source at this quote in a new tab)
“Foscarnet (FOS) treatment was initiated in all 8 patients (pending laboratory confirmation of ACV resistance) with some effect but associated with significant toxicity burden.” (opens the source at this quote in a new tab)
“Four patients presented again with recurrent HSV infection or no resolution.” (opens the source at this quote in a new tab)
“Three with recurrent HSV died from other causes while suffering from persistent oral HSV lesions.” (opens the source at this quote in a new tab)

Single-center series of 5 allogeneic transplant recipients: response to foscarnet with or without cidofovir

“Five cases of R/R HSV following HCT were identified.” (opens the source at this quote in a new tab)
“Foscarnet was used in all patients as initial therapy, whereas intravenous cidofovir was used as step-down therapy in two patients.” (opens the source at this quote in a new tab)
“Protracted courses of antivirals (foscarnet followed by cidofovir, or foscarnet alone) were required, with a median duration of therapy of five weeks (range: two to nine weeks); and although clinical improvement was noted in all the patients, complete healing and resolution of the infection were achieved in none.” (opens the source at this quote in a new tab)
“Three-month mortality was 80% (n=4), although none of the deaths were directly attributed to the HSV infection.” (opens the source at this quote in a new tab)

Allogeneic stem cell transplant recipients in France: response by foscarnet susceptibility

“Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period.” (opens the source at this quote in a new tab)
“All patients received foscarnet; 8 subsequently received cidofovir.” (opens the source at this quote in a new tab)
“Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients.” (opens the source at this quote in a new tab)
“In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients.” (opens the source at this quote in a new tab)

Acyclovir-resistant HSV-1 stomatitis after transplantation in Germany: intravenous foscarnet in 3 participants

“Among 214 consecutive HCT patients, 6 developed severe ACVr HSV-1 stomatitis (WHO grade III n = 1, WHO grade IV n = 5).” (opens the source at this quote in a new tab)
“Intravenous foscavir was used in 3 patients (first-line therapy, n = 1; second-line therapy, n = 2).” (opens the source at this quote in a new tab)
“Complete remission was reached by topical cidofovir (n = 3), topical foscavir (n = 1), and intravenous foscavir (n = 1), respectively.” (opens the source at this quote in a new tab)

Relapse after healing and resistance after repeated treatment: prescribing information

“Patients should be advised that FOSCAVIR is not a cure for HSV infections. While complete healing is possible, relapse occurs in most patients.” (opens the source at this quote in a new tab)
“Because relapse may be due to acyclovir-sensitive HSV, sensitivity testing of the viral isolate is advised.” (opens the source at this quote in a new tab)
“In addition, repeated treatment with FOSCAVIR has led to the development of resistance associated with poorer response.” (opens the source at this quote in a new tab)
“The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.” (opens the source at this quote in a new tab)

Foscarnet resistance among treated patients in a French surveillance network

“In 38% of the cases, the patients who excreted the ACV-resistant strains were treated with foscarnet (PFA), and 61% of them developed resistance to PFA.” (opens the source at this quote in a new tab)

Foscarnet resistance in transplant cohorts

“Four patients had laboratory-confirmed foscarnet resistance, by phenotypic assays.” (opens the source at this quote in a new tab)
“In 3 of the 4 patients, foscarnet resistance testing was performed after a median of 25 days (minimum, maximum: 20, 37) of foscarnet therapy.” (opens the source at this quote in a new tab)

“Six patients displayed foscarnet resistance, with an MIC (minimum inhibitory concentration) of >200 μg/mL, and these patients had been exposed to foscarnet within the previous month.” (opens the source at this quote in a new tab)

“Second-line therapy produced only partial responses, and in vitro evidence of foscarnet resistance developed rapidly in all 3 patients treated with foscarnet.” (opens the source at this quote in a new tab)
“Healing of lesions coincided with T-cell recovery.” (opens the source at this quote in a new tab)

“Seven patients did not respond to acyclovir, and 3 patients failed to respond to foscarnet.” (opens the source at this quote in a new tab)
“Isolates from 4 patients developed resistance to acyclovir/penciclovir, and 3 patients had foscarnet-resistant isolates.” (opens the source at this quote in a new tab)

Foscarnet-resistant HSV-2 in 6 people with HIV after prior foscarnet exposure

“Six human immunodeficiency virus-infected patients had clinical lesions of herpes simplex virus (HSV) type 2 that showed in vitro resistance to foscarnet.” (opens the source at this quote in a new tab)
“In each patient, lesions were unresponsive to foscarnet therapy or developed during daily suppressive foscarnet.” (opens the source at this quote in a new tab)
“Seven of 10 foscarnet-resistant isolates from 6 patients were susceptible to acyclovir in vitro, and 1 was of borderline susceptibility.” (opens the source at this quote in a new tab)
“Clinically significant resistance to foscarnet may occur in immunosuppressed patients with prior foscarnet exposure.” (opens the source at this quote in a new tab)

Boxed warning for foscarnet

“RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF FOSCAVIR. FREQUENT MONITORING OF SERUM CREATININE, WITH DOSE ADJUSTMENT FOR CHANGES IN RENAL FUNCTION, AND ADEQUATE HYDRATION WITH ADMINISTRATION OF FOSCAVIR IS IMPERATIVE.” (opens the source at this quote in a new tab)
“SEIZURES, RELATED TO ALTERATIONS IN PLASMA MINERALS AND ELECTROLYTES, HAVE BEEN ASSOCIATED WITH FOSCAVIR TREATMENT. THEREFORE, PATIENTS MUST BE CAREFULLY MONITORED FOR SUCH CHANGES AND THEIR POTENTIAL SEQUELAE. MINERAL AND ELECTROLYTE SUPPLEMENTATION MAY BE REQUIRED.” (opens the source at this quote in a new tab)
“FOSCAVIR IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR- RESISTANT HSV INFECTIONS.” (opens the source at this quote in a new tab)

Renal impairment: label warning and incidence with and without hydration

“Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during FOSCAVIR treatment.” (opens the source at this quote in a new tab)
“Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of FOSCAVIR.” (opens the source at this quote in a new tab)
“Approximately 33% of 189 patients with AIDS and CMV retinitis who received FOSCAVIR (60 mg/kg TID), without adequate hydration, developed significant impairment of renal function (serum creatinine ≥ 2.0 mg/dL).” (opens the source at this quote in a new tab)
“The incidence of renal impairment in subsequent clinical trials in which 1000 mL of normal saline or 5% dextrose solution was” (opens the source at this quote in a new tab)
“given with each infusion of FOSCAVIR was 12% (34/280).” (opens the source at this quote in a new tab)

Mineral and electrolyte abnormalities: label warning and incidence

“FOSCAVIR has been associated with changes in serum electrolytes including hypocalcemia (15–30%), hypophosphatemia (8–26%) and hyperphosphatemia (6%), hypomagnesemia (15– 30%), and hypokalemia (16–48%) (see WARNINGS section). The higher percentages were derived from those patients receiving hydration.” (opens the source at this quote in a new tab)
“FOSCAVIR may also be associated with a dose-related” (opens the source at this quote in a new tab)
“decrease in ionized serum calcium which may not be reflected in total serum calcium.” (opens the source at this quote in a new tab)
“This effect is likely to be related to chelation of divalent metal ions such as calcium by foscarnet.” (opens the source at this quote in a new tab)
“Patients should be advised to report symptoms of low ionized calcium such as perioral tingling, numbness in the extremities and paresthesias.” (opens the source at this quote in a new tab)
“Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances.” (opens the source at this quote in a new tab)
“The rate of FOSCAVIR infusion may also affect the decrease in ionized calcium. Therefore, an infusion pump must be used for administration to prevent rapid intravenous infusion (see DOSAGE AND ADMINISTRATION section). Slowing the infusion rate may decrease or prevent symptoms.” (opens the source at this quote in a new tab)

Seizures: label warning and incidence

“Seizures related to mineral and electrolyte abnormalities have been associated with FOSCAVIR treatment” (opens the source at this quote in a new tab)
“Several cases of seizures were associated with death. Cases of status epilepticus have been reported. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions.” (opens the source at this quote in a new tab)
“FOSCAVIR treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies” (opens the source at this quote in a new tab)
“The rate of seizures did not increase with duration of treatment.” (opens the source at this quote in a new tab)

QT prolongation, hypersensitivity, and other label warnings and precautions

“FOSCAVIR has been associated with prolongation of the QT interval, an ECG abnormality that has been associated with torsades de pointes, which has been reported during postmarketing surveillance for FOSCAVIR” (opens the source at this quote in a new tab)
“Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with FOSCAVIR.” (opens the source at this quote in a new tab)
“Serious acute hypersensitivity reactions (e.g., anaphylactic shock, urticaria, angioedema) have been reported postmarketing in patients receiving FOSCAVIR” (opens the source at this quote in a new tab)
“Local irritation and ulcerations of penile epithelium have been reported in male patients receiving FOSCAVIR, possibly related to the presence of drug in the urine.” (opens the source at this quote in a new tab)
“Due to the sodium content of FOSCAVIR (240 micromoles (5.5 mg) of sodium per mL), avoid FOSCAVIR use when intravenous infusion of a large amount of sodium or water may not be tolerated (e.g. in patients with cardiomyopathy).” (opens the source at this quote in a new tab)
“Anemia has been reported in 33% of patients receiving FOSCAVIR in controlled studies.” (opens the source at this quote in a new tab)

Adverse events in five controlled trials in AIDS and cytomegalovirus retinitis

“In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in Table 9. These figures were calculated without reference to drug relationship or severity.” (opens the source at this quote in a new tab)

Adverse event	Patients (n = 189)
Fever	“65%”
Nausea	“47%”
Anemia	“33%”
Diarrhea	“30%”
Abnormal renal function	“27%”
Vomiting	“26%”
Headache	“26%”
Seizures	“10%”

Severe adverse events in five controlled trials in AIDS and cytomegalovirus retinitis

Severe adverse event	Patients (n = 189)
Death	“14%”
Abnormal renal function	“14%”
Marrow suppression	“10%”
Anemia	“9%”
Seizures	“7%”

“Although death was specifically attributed to FOSCAVIR in only one case, other complications of FOSCAVIR (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths” (opens the source at this quote in a new tab)

Laboratory monitoring recommended in the prescribing information

“The majority of patients will experience some decrease in renal function due to FOSCAVIR administration. Therefore it is recommended that creatinine clearance, either measured or estimated using the modified Cockcroft and Gault equation based on serum creatinine, be determined at baseline, 2–3 times per week during induction therapy and once weekly during maintenance therapy, with FOSCAVIR dose adjusted accordingly” (opens the source at this quote in a new tab)
“FOSCAVIR should be discontinued if creatinine clearance drops below 0.4 mL/min/kg.” (opens the source at this quote in a new tab)
“It is recommended that a schedule similar to that recommended for serum creatinine (see above) be used to monitor serum calcium, magnesium, potassium and phosphorus.” (opens the source at this quote in a new tab)

Drug interactions that add to renal, calcium, and QT risk

“Because of foscarnet’s tendency to cause renal impairment, the use of FOSCAVIR should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B, cyclosporine, acyclovir, methotrexate, tacrolimus and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient.” (opens the source at this quote in a new tab)
“Because FOSCAVIR can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels (e.g., intravenous pentamidine).” (opens the source at this quote in a new tab)
“Because of the risk of QT prolongation and the potential for torsades de pointes, the use of FOSCAVIR should be avoided in combination with agents known to prolong the QT interval including Class IA (e.g., quinidine or procainamide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents, phenothiazines, tricyclic antidepressants, and certain macrolides and fluoroquinolones.” (opens the source at this quote in a new tab)

Multicenter cohort of 31 foscarnet-treated episodes: adverse events and discontinuation

“At least 1 adverse event occurring during foscarnet therapy was reported in 26 of 31 (84%) episodes including 23 episodes (74%), during which at least 1 adverse event was considered drug related.” (opens the source at this quote in a new tab)
“The most frequent adverse events were related to electrolyte disturbance and kidney function and a majority of these were attributed to foscarnet therapy.” (opens the source at this quote in a new tab)
“Foscarnet was discontinued in 10 episodes (32%) due to an adverse event including in 6 episodes (19%) due to kidney disorders.” (opens the source at this quote in a new tab)
“Foscarnet was not discontinued due to electrolyte disturbances, but electrolyte adverse events attributed to foscarnet occurred in 19 of 31 (61%) HSV episodes including hypocalcemia and hypophosphatemia, which both occurred in 11 of 31 episodes (35%).” (opens the source at this quote in a new tab)
“No episodes of seizure were reported.” (opens the source at this quote in a new tab)
“There were 11 episodes (35%) during which at least 1 serious adverse event occurred, most of which were due to infections or respiratory disorders.” (opens the source at this quote in a new tab)
“Two episodes of HSV that were complicated by serious adverse events were due to acute kidney injury, 1 of which led to foscarnet discontinuation.” (opens the source at this quote in a new tab)
“Nine study subjects had 13 adverse events leading to death, none of which were considered to be related to foscarnet.” (opens the source at this quote in a new tab)

Multicenter cohort of 31 foscarnet-treated episodes: electrolyte and kidney adverse events

Adverse event	Any adverse event, number (%) of 31 episodes	Foscarnet-related adverse event, number (%) of 31 episodes
Electrolyte disorders	“20 (65)”	“19 (61)”
Hypocalcemia	“11 (35)”	“11 (35)”
Hypokalemia	“9 (29)”	“8 (26)”
Hypomagnesemia	“5 (16)”	“5 (16)”
Hypophosphatemia	“11 (35)”	“11 (35)”
Renal and urinary disorders	“13 (42)”	“9 (29)”

“Kidney injury includes the Medical Dictionary for Regulatory Activities classifications: acute kidney injury, renal impairment, increased blood creatinine, azotemia, and worsening of chronic kidney disease.” (opens the source at this quote in a new tab)

Multicenter cohort of 31 foscarnet-treated episodes: inpatient management and monitoring

“Furthermore, foscarnet therapy given over adequate durations to treat resistant HSV typically requires careful management in the inpatient setting that can lead to prolonged hospitalization.” (opens the source at this quote in a new tab)
“Monitoring of renal function and electrolytes at least 2–3 times a week, vigorous hydration, and electrolyte repletion are necessary and require clinicians to be vigilant, especially when foscarnet is administered in the outpatient setting.” (opens the source at this quote in a new tab)

Real-world cohort of 125 hematopoietic cell transplant recipients: toxicity during 109 foscarnet courses

“Among 109 foscarnet courses, ≥1 toxicity was reported during 75 courses (68.8%).” (opens the source at this quote in a new tab)
“Discontinuation because of toxicity was reported in 33 (30.3%) courses.” (opens the source at this quote in a new tab)
“The most common toxicity or intolerance was renal function abnormalities reported during 44 courses (40.4%), followed by electrolyte abnormalities and gastrointestinal symptoms (nausea and anorexia).” (opens the source at this quote in a new tab)
“Fourth, reporting of toxicity could be prone to misclassification bias because no laboratory cutoff values were used.” (opens the source at this quote in a new tab)

Single-center cohort of 18 allogeneic transplant recipients: hospitalization, kidney injury, and hemodialysis

“Complications derived from acyclovir-resistant HSV infection and its treatment included hospitalization in nine (50%) patients, acute kidney injury secondary to antivirals in nine (50%) patients, and hemodialysis subsequent to kidney injury in four (22%) patients.” (opens the source at this quote in a new tab)
“Of the whole cohort, nine patients (50%) died within 1 year after HSV infection, and none of those nine had clinical responses.” (opens the source at this quote in a new tab)

Single-center cohort of 18 allogeneic transplant recipients: renal toxicity among foscarnet recipients as tabulated in a review

“11 out of 16 patients who received i.v. FOS experienced renal toxicity” (opens the source at this quote in a new tab)
“Four out of five patients who received i.v. FOS and i.v. CDV required haemodialysis.” (opens the source at this quote in a new tab)

Nephrotoxicity, electrolyte imbalance, and genital ulceration as summarized in a review

“FOS is associated with significant adverse events, foremost nephrotoxicity, secondary to interstitial nephritis and acute renal tubular necrosis, electrolyte imbalances, and skin ulcerations, mainly in the genital areas” (opens the source at this quote in a new tab)

Single-center series of 5 allogeneic transplant recipients: acute renal failure and electrolyte disturbance

“Two patients (40%) developed acute renal failure related to antiviral therapy requiring dose adjustments for creatinine clearance, and electrolyte disturbances were common (80%)” (opens the source at this quote in a new tab)
“Despite prolonged courses of foscarnet or cidofovir, with long hospital stays, only half of the patients presented here had clearance of HSV viremia, and none achieved complete healing of the mucocutaneous lesions.” (opens the source at this quote in a new tab)

Acute kidney injury and electrolyte abnormalities in transplant recipients given foscarnet for cytomegalovirus or human herpesvirus 6

“This retrospective, single-center, observational study at Stanford University Medical Center assessed HCT recipients who received foscarnet between January 2009 and May 2019.” (opens the source at this quote in a new tab)
“Twenty-eight of 45 patients (62.2%) who received continuous-infusion foscarnet experienced an acute kidney injury (AKI) as defined by the Kidney Disease Improving Global Outcomes classification, compared with 39 of 62 patients (62.9%) who received conventional infusion (P = .94).” (opens the source at this quote in a new tab)
“The incidences of hypocalcemia (71.1% versus 79.0%; P = .35), hypophosphatemia (71.1% versus 74.1%; P = .72), hypomagnesemia (77.8% versus 87.1%; P = .20) and hypokalemia (82.2% versus 74.1%; P = .33) was similar in the 2 groups.” (opens the source at this quote in a new tab)