Summary

Before pritelivir, intravenous foscarnet was the only medication approved by the FDA for refractory or resistant HSV infection. Among 125 hematopoietic cell transplant recipients at 7 United States centers, 69 (55.2%) healed completely at a median of 38 days, 40 (32.0%) died on therapy, and 27 of the 69 who healed (39.1%) had a recurrence within 1 year. Of 31 foscarnet-treated episodes in a second cohort, 15 (48%) healed, 20 (65%) had electrolyte disturbance, 13 (42%) had kidney injury, and 10 (32%) ended in discontinuation for an adverse event. Foscarnet is infused intravenously by pump with hydration. In a French surveillance network, 7 of 12 people given foscarnet for acyclovir-resistant strains excreted foscarnet-resistant strains. Guideline alternatives are rated BIII or CIII, and topical cidofovir, trifluridine, and foscarnet are not commercially available.

Healing, death on therapy, and time to healing in a United States multicenter transplant cohort

“Sixty-nine patients (55.2%) achieved our primary endpoint of complete healing. 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)
“In the contemporary cohort (2017–2024; N = 90), the median time to healing was 37.5 days (Q1, Q3: 23, 63), with cumulative incidence of healing of 19.1% at day 28, 30.6% at day 42 and 52.6% at day 90.” (opens the source at this quote in a new tab)

Recurrence and death within one year of healing in the multicenter transplant cohort

“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)
“The time to first recurrence was a median of 61 days (Q1, Q3: 29, 97; minimum, maximum: 10, 298).” (opens the source at this quote in a new tab)
“Of a total of 30 recurrent episodes, 7 had acyclovir resistance testing and acyclovir resistance was confirmed in 5 episodes.” (opens the source at this quote in a new tab)

Treatment sequence before second-line therapy in the multicenter transplant cohort

“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%). 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)
“One-third of patients received high-dose IV acyclovir before second-line therapies, despite limited data for efficacy of high-dose IV acyclovir for acyclovir-resistant HSV.” (opens the source at this quote in a new tab)
“The number of antiviral courses and duration of exposure highlight the burden of therapy for refractory HSV infections.” (opens the source at this quote in a new tab)

Healing, recurrence, and pain in foscarnet-treated episodes in a United States multicenter study

“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 (Table 4).” (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. 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)

Deaths in the foscarnet-treated cohort

“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)

Response, treatment duration, and one-year mortality in a United States cancer center cohort

“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)
“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)
“Causes of death included bacterial infections (n=4), heart failure (n=1), graft failure with diffuse alveolar hemorrhage (n=1), unknown causes (n=2), and HSV hepatitis with disseminated infection (n=1).” (opens the source at this quote in a new tab)

Delay to susceptibility testing and to a change of therapy

“Acyclovir resistance was suspected and susceptibility analyses ordered at a median of 15 days after HSV infection was clinically diagnosed (IQR: 0–96 days).” (opens the source at this quote in a new tab)
“The mean time to transition of antiviral therapy was 27 days (IQR: 10–70 days) in both groups but 9 days (IQR: 2–46) in the rapid responders, in contrast to 28 days (IQR: 7–96) in the slow and non-responders (p=0.15).” (opens the source at this quote in a new tab)

“Antiviral resistance by phenotypic assays take weeks to perform; thus, results are not available in real time for treatment decisions” (opens the source at this quote in a new tab)

Mortality in a series of 18 participants with hematologic disease with acyclovir-resistant infection

“Foscarnet was used for treating ACV‐resistant HSV in all patients, often combined with other antivirals (e.g., ganciclovir, valacyclovir, or cidofovir) depending upon clinical findings, and the patient's medical status.” (opens the source at this quote in a new tab)
“Eleven patients died within less than 6 months (median 3 months) from diagnosis of ACV resistance.” (opens the source at this quote in a new tab)
“While the direct cause of death was not recorded, oral lesions associated with HSV infection were documented in close proximity to the date of death in eight of these patients.” (opens the source at this quote in a new tab)

Healing and mortality in a series of five allogeneic transplant recipients

“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%, and none of the patients survived 12 months from the R/R HSV diagnosis, although none of the deaths were directly attributed to the HSV infection.” (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)

Outcomes with foscarnet in eight allogeneic transplant recipients in the United Kingdom

“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. 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)
“ACV resistance was clinically suspected at a median of 25 [range,16-109] days after initial HSV diagnosis and subsequently laboratory confirmed at a median of 25 (range,10-59) days.” (opens the source at this quote in a new tab)

Complete response to foscarnet and cidofovir in allogeneic stem cell transplant recipients in France

“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)
“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)
“No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response.” (opens the source at this quote in a new tab)

Clinical resistance and outcome in 75 allogeneic stem cell transplant recipients

“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)
“Clinical as well as in vitro resistance to antiviral drugs is common in patients with severe GVHD and is associated with a poor outcome.” (opens the source at this quote in a new tab)

One-hundred-day death rates by acyclovir susceptibility after transplantation in Japan

“The 100-day death rates of HSCT patients without HSV-1 shedding, those with only ACV-sensitive HSV-1 shedding, and those with ACVr HSV-1 shedding were 31%, 39%, and 64%, respectively.” (opens the source at this quote in a new tab)

Recurrence during long-term follow-up in HIV infection

“Initially, 11 patients were treated with foscarnet and two with cidofovir. The median follow-up was 67 months (6-145).” (opens the source at this quote in a new tab)
“All patients recurred, 10 presenting at least one acyclovir-resistant HSV recurrence.” (opens the source at this quote in a new tab)
“The median number of acyclovir-resistant HSV recurrences per patient was 2 (0 - 5).” (opens the source at this quote in a new tab)

Healing and relapse with foscarnet as stated in its label

“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. 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)
“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)

Foscarnet boxed warning: renal impairment and seizures

“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)

Foscarnet label: rates of renal impairment, electrolyte changes, and seizures

“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)
“given with each infusion of FOSCAVIR was 12% (34/280).” (opens the source at this quote in a new tab)
“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%)” (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 majority of patients will experience some decrease in renal function due to FOSCAVIR administration.” (opens the source at this quote in a new tab)

Foscarnet label: genital ulceration

“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. Cases of male and female genital irritation/ulceration have been reported in patients receiving FOSCAVIR.” (opens the source at this quote in a new tab)

Foscarnet label: intravenous infusion, infusion pump, hydration, and laboratory monitoring

“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)
“FOSCAVIR is administered by controlled intravenous infusion, either by using a central venous line or by using a peripheral vein.” (opens the source at this quote in a new tab)
“An infusion pump must be used to control the rate of infusion.” (opens the source at this quote in a new tab)
“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.” (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)

Foscarnet adverse events and discontinuation in the United States multicenter study

“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)
“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)
“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)

Most common adverse events during foscarnet therapy by organ system in 31 episodes

Adverse event	Any adverse event, number (%)	Foscarnet-related adverse events, number (%)
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)”
Kidney injury	“13 (42)”	“9 (29)”

Toxicity and discontinuation during foscarnet and cidofovir courses in the multicenter transplant cohort

“Among 109 foscarnet courses, ≥1 toxicity was reported during 75 courses (68.8%). 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)
“Among 6 IV cidofovir courses, renal function abnormalities were reported during 3 courses (50%). One of 6 courses of IV cidofovir was discontinued because of the renal function abnormalities.” (opens the source at this quote in a new tab)

Hospitalization, acute kidney injury, and hemodialysis in the United States cancer center cohort

“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)

Renal failure and electrolyte disturbance in the series of five transplant recipients

“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)

Acute kidney injury with foscarnet given for any herpesvirus infection after transplantation

“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 average number of inpatient antiviral days was 7.9 days (range, 0 to 58 days) for the CI group and 8.3 days (range, 0 to 45 days) in the INT group (P = .50).” (opens the source at this quote in a new tab)
“At our institution, CI permitted treatment on an outpatient basis, whereas INT with hydration could not feasibly be provided by home care given the slow infusion rate recommended to minimize the risk of nephrotoxicity.” (opens the source at this quote in a new tab)

Foscarnet for resistant or refractory cytomegalovirus infection in transplant recipients

“Median duration of foscarnet was 32 days. Virologic failure occurred in 13/39 (33%) and relapses of viremia occurred in 31%.” (opens the source at this quote in a new tab)
“Renal dysfunction occurred in 20/39 (51%) by end of treatment and in 7/25 (28%) after 6 months.” (opens the source at this quote in a new tab)

Intravenous administration and 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)
“Health care resource utilization and costs associated with foscarnet were beyond the scope of this study but should be quantified in future studies” (opens the source at this quote in a new tab)

“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)

“The oral bioavailability of FOS is poor and, thus, it is only available as an intravenous formulation. Foscarnet is nephrotoxic and induces electrolyte disorders.” (opens the source at this quote in a new tab)

Intravenous cidofovir: boxed warning, contraindications, and outpatient use

“RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF CIDOFOVIR INJECTION. CASES OF ACUTE RENAL FAILURE RESULTING IN DIALYSIS AND/OR CONTRIBUTING TO DEATH HAVE OCCURRED WITH AS FEW AS ONE OR TWO DOSES OF CIDOFOVIR INJECTION.” (opens the source at this quote in a new tab)
“Initiation of therapy with cidofovir injection is contraindicated in patients with serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria)” (opens the source at this quote in a new tab)

“Systemic cidofovir requires weekly IV administration and, although it could theoretically be given in the outpatient setting, concerns for nephrotoxicity and limited efficacy data hinder its applicability for refractory HSV.” (opens the source at this quote in a new tab)

Foscarnet resistance after foscarnet exposure: label statement

“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)

Herpes simplex virus DNA polymerase substitutions conferring foscarnet resistance with cross-resistance to acyclovir or cidofovir

Cross-resistance	Virus and protein	Substitutions
Cross-resistant to acyclovir	HSV-1 pUL30	“E597D, S599L, A605V, D672N, R700G, L702H, V714M, V715G, A719T/V, S724N, L774F, L778M, D780N, L782I, P797T, E798K, L802F, V813M, V817M, Y818C, T821M, G841C/S, R842S, S889A, F891C/Y, V892M, D907V, A910V/T, SRA914-916LCV, Y941H, V958L, V959H”
Cross-resistant to acyclovir	HSV-2 pUL30	“A724T, S725G, S729N, Q732R, L783M, D785N, T844I, D912V”
Marginally cross-resistant to cidofovir	HSV-1 pUL30	“V714M, A719V, S724N, L778M, L802F, Y818C, T821M, G841S”
Marginally cross-resistant to cidofovir	HSV-2 pUL30	“L783M”

Foscarnet resistance among foscarnet-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)
“Of the 12 ACV-resistant patients treated with PFA, 7 excreted PFA-resistant strains (Table 6).” (opens the source at this quote in a new tab)
“Treatment with ACV had been administered to 10 of the 11 patients, and among the 5 patients who had been treated with PFA, 2 excreted PFA-resistant strains.” (opens the source at this quote in a new tab)

Foscarnet resistance in transplant cohorts

“Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients.” (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)

“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)

“Four patients had laboratory-confirmed foscarnet resistance, by phenotypic assays. 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)

Foscarnet-resistant infection in patients with AIDS

“Six human immunodeficiency virus-infected patients had clinical lesions of herpes simplex virus (HSV) type 2 that showed in vitro resistance to foscarnet. 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)

Shared DNA polymerase target and cross-resistance among approved antivirals

“All antivirals approved for the treatment of HSV infections have the same target, i.e. the viral DNA polymerase, and cross-resistance to different antivirals has been described, complicating therapy of acyclovir resistant strains.” (opens the source at this quote in a new tab)

“Mutants with alterations in both HSV TK and DNA pol can also occur, resulting in double resistance to both ACV and FOS.” (opens the source at this quote in a new tab)
“In addition, the mutations S724N and L778M which conferred cross-resistance to ACV and FOS also caused reduced susceptibility to cidofovir and adefovir” (opens the source at this quote in a new tab)

Evidence base behind treatment recommendations

“Apart from two small randomized controlled trials in the 1990s that looked at treatment with systemic foscarnet and topical cidofovir in patients living with human immunodeficiency virus, all treatment recommendations for R/R HSV infections are based on observational studies and case reports.” (opens the source at this quote in a new tab)
“However, data on using FOS for R/R HSV infections in HCT recipients are based on observational studies and case series” (opens the source at this quote in a new tab)
“owing to the lack of randomized clinical trials in this patient population.” (opens the source at this quote in a new tab)

“Published guidelines encompass a wide range of hosts and are limited by the lack of controlled studies or approved therapies for refractory HSV” (opens the source at this quote in a new tab)

“Additionally, treatment outcomes for resistant HSV with these regimens remain understudied, with descriptions often limited to case reports or case series that are impacted by success bias.” (opens the source at this quote in a new tab)

“Alternative therapeutic approaches, such as foscarnet, cidofovir, topical cidofovir, optimised acyclovir dosing, and helicase-primase inhibitors offer promising options but require further investigations.” (opens the source at this quote in a new tab)

Guideline ratings of the alternatives to foscarnet

“IV cidofovir is a potential alternative (CIII).” (opens the source at this quote in a new tab)
“Topical imiquimod, cidofovir, trifluridine, and foscarnet also have been used successfully to treat external lesions (BIII), although prolonged application for 21 to 28 days or longer may be required.” (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)

“The efficacy, safety, and durability of the therapeutic response of these agents has yet to be determined in prospective controlled trials.” (opens the source at this quote in a new tab)

Topical alternatives: commercial availability and supporting evidence

“Topical formulations of trifluridine, cidofovir, and foscarnet are not commercially available.” (opens the source at this quote in a new tab)
“Topical cidofovir, foscarnet, and trifluridine must be compounded in a pharmacy.” (opens the source at this quote in a new tab)

“Topical antiviral preparations may be occasionally used as an adjunct to systemic antivirals or as step-down therapy, with scant supporting evidence” (opens the source at this quote in a new tab)

“Eight (33 percent) patients developed new lesions outside of the treatment area while on study, reflecting the local nature of this therapy.” (opens the source at this quote in a new tab)

Federal guideline statements on nephrotoxicity and monitoring of systemic alternatives

“Systemic foscarnet and cidofovir are nephrotoxic medications; treatment should be given in consultation with an infectious diseases specialist (AIII) and with frequent laboratory monitoring” (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)

“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)

Consensus working group statement on alternative treatment

“Refractory and/or resistant HSV infections in HCT recipients were associated with poor outcomes, such as recurrent infections, prolonged antiviral therapy, renal injury, higher hospitalization risk, and even death” (opens the source at this quote in a new tab)
“Alternative treatment of R/R HSV infection in immunocompromised hosts is limited to drugs such as FOS and cidofovir (CDV), which may lead to severe side effects such as renal dysfunction” (opens the source at this quote in a new tab)
“In addition to serious toxicities, 1 recent study reported suboptimal responses while on or after receiving FOS for R/R HSV infections” (opens the source at this quote in a new tab)

Review statements on the toxicity of foscarnet and cidofovir

“FOS is the only FDA-approved medication for R/R HSV infections to date.” (opens the source at this quote in a new tab)
“The management of R/R HSV infection is particularly challenging owing to limited treatment options (systemic foscarnet [FOS] or cidofovir [CDV] and topical agents), which are associated with severe toxicity, including renal injury, electrolyte disturbances, myelosuppression, and treatment-induced genital lesions” (opens the source at this quote in a new tab)
“The limited available data and the severe toxicity of CDV underscore the need for further investigation into the optimal conditions and patient profiles for successful CDV intervention for HCT recipients with R/R HSV infections.” (opens the source at this quote in a new tab)

“However, both drugs have several adverse effects, including nephrotoxicity, electrolyte disturbances, mucosal ulceration, nausea, and vomiting (Table 1)” (opens the source at this quote in a new tab)

“Due to its significant adverse effects (including nephrotoxicity, electrolyte disturbances, genital ulceration, and others), its use for HSV and VZV is limited to treatment of severe or disseminated infection with proven or suspected resistance to acyclovir” (opens the source at this quote in a new tab)

“Current treatments, such as acyclovir, target viral DNA polymerase but have limited efficacy and are susceptible to resistance, especially in immunosuppressed populations. Rescue therapies such as foscarnet exhibit limiting toxicity.” (opens the source at this quote in a new tab)

Investigator conclusions on unmet need in cohort studies

“Our study highlights the challenges of managing refractory HSV post-HCT during the study timeframe, and underscores the unmet need for safer, more effective, and orally bioavailable therapies for refractory HSV.” (opens the source at this quote in a new tab)

“Foscarnet is the preferred treatment choice for resistant HSV, but as demonstrated in this cohort, it is limited in efficacy and is associated with substantial renal and electrolyte toxicities.” (opens the source at this quote in a new tab)
“In summary, this cohort of 29 immunocompromised individuals treated with foscarnet for 31 episodes of HSV demonstrated the limited efficacy and substantial toxicity of foscarnet therapy, and the unmet need for a less toxic, orally bioavailable therapy for resistant/refractory HSV infection.” (opens the source at this quote in a new tab)

“A prolonged immunosuppressed state following T-deplete HSCTs alongside extended use of ACV, early onset systemic HSV infection, presence of cGVHD, and treatment toxicities pose a significant challenge to the management of ACV resistant HSV infections and alternative effective antiviral options remains an unmet need in this clinical setting.” (opens the source at this quote in a new tab)

“Current antivirals for R/R HSV infections have suboptimal efficacy and safety profiles.” (opens the source at this quote in a new tab)

“Treatment of aciclovir-resistant anogenital HSV disease is challenging, as resistance to alternative treatments may occur, and effective treatment generally involves intravenous therapy with relatively toxic agents such as foscarnet.” (opens the source at this quote in a new tab)