Evicenter
P&T meetings

Hovilpri (pritelivir)

Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults

Also known as AIC316
Last updated
239 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatmentCurrent treatment options and standard of care

Compounded topical antivirals (Cidofovir, trifluridine, and foscarnet)

34 evidence topics · 25 sources

National Institutes of Health opportunistic infections guideline: topical cidofovir, trifluridine, and foscarnet as alternative therapies rated BIII

“Topical cidofovir 1% gel once daily (BIII)” (opens the source at this quote in a new tab)

“Topical trifluridine 1% three times a day (BIII)” (opens the source at this quote in a new tab)

“Topical foscarnet 1% five times a day (BIII)” (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)

“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)

Centers for Disease Control and Prevention sexually transmitted infections guideline: compounded cidofovir gel 1%

“Topical cidofovir gel 1% can be applied to lesions 2–4 times daily; however, cidofovir must be compounded at a pharmacy” (opens the source at this quote in a new tab)

European Conference on Infections in Leukaemia recommendations: topical trifluridine and cidofovir gel rated CIII
ResistanceRegimenRatingRestriction
Resistance to acyclovir or famciclovir“Topical trifluridine 5% ophtalmic solution q8h”“(CIII)”“For accessible cutaneous lesions”
Resistance to acyclovir or famciclovir“Topical cidofovir gel 0.3% or 1% once daily”“(CIII)”“For accessible cutaneous lesions”
Resistance to foscarnet“Topical trifluridine 5% ophtalmic solution q8h”“(CIII)”“For accessible cutaneous lesions”
Resistance to foscarnet“Topical cidofovir gel 0.3% or 1% once daily”“(CIII)”“For accessible cutaneous lesions”
United Kingdom anogenital herpes guideline: foscarnet cream and cidofovir gel rated 1A and trifluorothymidine rated 2D

“Both topical 1% foscarnet cream” (opens the source at this quote in a new tab)

“and 1% cidofovir gel” (opens the source at this quote in a new tab)

“have been shown to produce significant benefits in lesion healing, pain reduction and virological effect in drug resistant herpes in people living with HIV (1A).” (opens the source at this quote in a new tab)

“There is limited evidence to support the use of topical trifluorothymidine alone or in combination with interferon-alpha (2D).” (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)

“HSV associated IRIS may be unresponsive to previously effective anti-herpes viral therapy in the absence of increased antiviral resistance. Management is difficult but topical cidofovir may be effective.” (opens the source at this quote in a new tab)

Absence of commercial topical formulations and extemporaneous compounding

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

“Extemporaneous compounding of topical products can be prepared using trifluridine ophthalmic solution and the IV formulation of cidofovir and foscarnet.” (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)

Food and Drug Administration decision on topical cidofovir and compounding hazards

“An application to approve the use of topical cidofovir for acyclovir-resistant herpes virus infection was denied by the US Food and Drug Administration owing to the lack of phase III clinicla trial data.” (opens the source at this quote in a new tab)

“The manufacturer stated that, as of 1997, no further controlled studies were planned or in progress to evaluate topical cidofovir in herpes simplex infections.” (opens the source at this quote in a new tab)

“Because of the mutagenic properties of cidofovir, compounding the preparation is considered hazardous.” (opens the source at this quote in a new tab)

“Since most retail pharmacies do no have the safety equipment necessary to compound hazardous preparations, a compounding pharmacist can play a vital role in preparing topical cidofovir cream or gel.” (opens the source at this quote in a new tab)

Cidofovir gels evaluated in recurrent genital herpes and their commercial status

“The safety and efficacy of single topical applications of 1, 3, and 5% cidofovir gels have been evaluated for the treatment of early, lesional, recurrent genital herpes” (opens the source at this quote in a new tab)

“but they are not commercially available.” (opens the source at this quote in a new tab)

Labeled indication and formulation of cidofovir injection

“Cidofovir is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).” (opens the source at this quote in a new tab)

“Cidofovir injection, USP is a sterile, hypertonic aqueous solution for intravenous infusion only.” (opens the source at this quote in a new tab)

Labeled formulation of foscarnet

“FOSCAVIR INJECTION is a sterile, isotonic aqueous solution for intravenous administration only.” (opens the source at this quote in a new tab)

Labeled indication and formulation of trifluridine ophthalmic solution

“Trifluridine Ophthalmic Solution is indicated for the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2.” (opens the source at this quote in a new tab)

“Trifluridine sterile ophthalmic solution contains 1% trifluridine in an aqueous solution with acetic acid and sodium acetate (buffers), sodium chloride, and thimerosal 0.001% (added as a preservative).” (opens the source at this quote in a new tab)

Off-label status, dose, and monitoring of topical antivirals as tabulated in a review
PreparationDoseClinically significant adverse reactionsMonitoringFDA approval or off-label use
Cidofovir 0.3% to 5.0% cream“1–4 times daily”“Nephrotoxicity: renal insufficiency”“Serum creatinine”“Electrolytes”“Off-label use”
Cidofovir 3% oral rinse“Swish and spit 2–4 times daily”“Nephrotoxicity: renal insufficiency”“Serum creatinine”“Electrolytes”“Off-label use”
Foscarnet 1.0% to 2.5% cream or mouthwash“4–6 times daily”“Dermatologic: local skin/mucosal reactions”“Local reaction”“Off-label use”
Trifluridine 1% to 5% ophthalmic solution“Three times daily”“Dermatologic/ophthalmic: local skin and eye reactions”“Local reaction”“Off-label use”
Guideline-recommended topical regimens and their evidence base as described in a review

“The Infectious Diseases Society of America (IDSA) recommends applying 1% CDV cream or gel (not commercially available) once daily or oral rinse up to four times daily for ACV-resistant mucocutaneous HSV infections” (opens the source at this quote in a new tab)

“FOS cream at a concentration of 1.0–2.5% (not commercially available) applied five times a day is another recommended option for ACV-resistant mucocutaneous HSV infections” (opens the source at this quote in a new tab)

“Some guidelines suggest the off-label use of topical 1–5% trifluridine (not commercially available) three times a day as an alternative option for R/R HSV mucocutaneous lesions” (opens the source at this quote in a new tab)

“based on a few reported cases of patients with HIV and refractory HSV-2 hypertrophic lesions” (opens the source at this quote in a new tab)

Cidofovir gel: randomized, double-blind, placebo-controlled trial in AIDS, design

“The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial.” (opens the source at this quote in a new tab)

“Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days.” (opens the source at this quote in a new tab)

Cidofovir gel: lesion healing, viral shedding, and pain in the randomized trial

“Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031).” (opens the source at this quote in a new tab)

“Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004).” (opens the source at this quote in a new tab)

“For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively).” (opens the source at this quote in a new tab)

“Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042).” (opens the source at this quote in a new tab)

Cidofovir gel: application-site reactions in the randomized trial

“Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting.” (opens the source at this quote in a new tab)

Topical cidofovir: first reports in infection resistant to acyclovir and foscarnet

“One patient with AIDS suffered from a perineal lesion due to infection with herpes simplex virus type 2 (HSV-2) and did not respond to acyclovir and was intolerant of foscarnet.” (opens the source at this quote in a new tab)

“A bone marrow transplant recipient developed orofacial lesions due to infection with herpes simplex virus type 1 (HSV-1) that failed to respond to therapy with both acyclovir and foscarnet.” (opens the source at this quote in a new tab)

“After topical application of HPMPC, the HSV-2 lesions completely resolved. However, the lesions recurred 3 weeks later, and, upon subsequent treatment with HPMPC, regressed.” (opens the source at this quote in a new tab)

“Following local HPMPC treatment, the lesions regressed, but after 1 week, a second course of topical HPMPC therapy had to be instituted for recurrent infection.” (opens the source at this quote in a new tab)

Topical cidofovir and foscarnet: stomatitis after allogeneic hematopoietic cell transplantation

“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)

“ACVr stomatitis was treated topically with first-line (n = 4) or second-line (n = 2) cidofovir. Topical foscavir cream was applied as first-line (n = 1) or second-line (n = 1) therapy.” (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)

“Five of the 6 patients died due to progression of leukemia.” (opens the source at this quote in a new tab)

“This analysis shows that topical treatment with cidofovir or foscavir might be a sufficient first-line therapy approach in ACVr HSV-1 stomatitis. It might serve as a less toxic alternative to intravenous foscavir.” (opens the source at this quote in a new tab)

Topical cidofovir: oral rinse in a transplant recipient with multidrug-resistant infection

“We present a case of serious treatment-refractory acyclovir- and foscarnet-resistant herpes simplex virus (HSV) type-1 orolingual infection that responded to oral cidofovir rinses after failure of acyclovir and foscarnet therapy.” (opens the source at this quote in a new tab)

“The use of 3% cidofovir in a saline rinse for refractory mucosal HSV infection appears promising but needs prospective evaluation.” (opens the source at this quote in a new tab)

Topical cidofovir: perianal ulcer in a transplant recipient

“Cidofovir is marketed as an injectable for intravenous use; however, there is a topical cidofovir formulation utilized for viral dermatologic infections.” (opens the source at this quote in a new tab)

“After 1 week of therapy with cidofovir gel, the patient's ulcer was clinically improved, and the lesion was negative for herpes simplex virus transcripts by real-time polymerase chain reaction testing.” (opens the source at this quote in a new tab)

Topical cidofovir: oral infection in a transplant recipient unable to tolerate systemic antivirals

“Oral symptoms and lesions were repeatedly reduced when topical cidofovir was used, strongly supporting the effect of cidofovir used in a host who could not tolerate systemic antiviral medications.” (opens the source at this quote in a new tab)

Topical cidofovir and foscarnet in transplant recipients as tabulated in a review
ReportTopical regimenSystemic concurrent therapyTopical treatment adverse effectsOutcome
One recipient with oral HSV-1 infection (2020 report)“CDV 1% mouthwash for 3 months and topical cream for 2 months”“None”“None”“No resolution”
One recipient with oral HSV-1 infection (2016 report)“CDV rinse (3%/15 cm3 swish and spit four times a day)”“i.v. FOS in the first episode”“None”“Improvement with concurrent i.v. FOS. In the next episode, a resolution on CDV rinses monotherapy.”
One recipient with oral infection (2016 report of kidney injury)“CDV 5% oral gel twice a day”“i.v. ACV 5 mg/kg three times a day”“AKI, glucosuria”“No resolution”
One recipient with perianal infection (2016 report of kidney injury)“CDV cream 3–5% 2–4 times daily”“i.v. FOS, oral VACV”“AKI, glucosuria haemodialysis, and kidney biopsy revealed ATN”“Improvement”
One recipient with perianal HSV-2 infection (2011 report)“CDV 2%, ointment twice a day for 3 weeks”“None”“None”“Resolution”
One recipient with oral HSV-1 infection (2007 report)“CDV 3% rinse solution twice a day for 5 days”“None”“None”“Resolution”
Six recipients with oral HSV-1 infection (2020 series)“CDV 3% oral rinse solution twice a day and 1% CDV gel twice a day”“i.v. ACV (2 patients) and i.v. FOS (1 patient)”“None”“Response in 4/6 and resolution in 3/6”
One recipient with perianal HSV-1 infection (2013 report)“CDV 1% gel every 6 hours”“i.v. FOS”“None”“Resolution”
Nine of 18 recipients (2018 cohort)“CDV 1–3% once daily”“i.v. FOS, oral VACV or i.v. CDV”“AKI (concurrent i.v. FOS or CDV)”“Unspecified”
One recipient with oral HSV-1 infection, topical foscarnet (2023 report)“FOS mouthwash daily for 20 days”“i.v. CDV”“Not specified”“Not specified”
Two recipients with oral HSV-1 infection, topical foscarnet (2020 series)“FOS 2% cream”“None”“None”“Response in 2/2, resolution in 1/2”
Topical cidofovir: results and kidney injury in transplant recipients as summarized in a review

“In HCT recipients, the use of topical CDV (1–5%) has produced mixed results” (opens the source at this quote in a new tab)

“and could lead to acute kidney injury and glycosuria, suggesting proximal tubule injury, as reported in one patient” (opens the source at this quote in a new tab)

Topical cidofovir: irreversible acute kidney injury in two immunocompromised participants

“The safety and efficacy of topical cidofovir has been described in a limited number of patients.” (opens the source at this quote in a new tab)

“We present two cases of multidrug-resistant herpes simplex virus infections that responded to topical cidofovir therapy yet resulted in irreversible acute kidney injury.” (opens the source at this quote in a new tab)

Topical cidofovir: duration and renal monitoring in a transplant cohort

“The duration of topical cidofovir varied between patients and ranged between 5 and 58 days with close follow-up of their renal function.” (opens the source at this quote in a new tab)

“Recurrent HSV infection occurred in four patients (22%), all of whom had foscarnet-resistant HSV infection, an underlying diagnosis of GvHD, and were treated with parenteral or topical cidofovir therapy.” (opens the source at this quote in a new tab)

Topical cidofovir: compounding logistics and cost in a single-center series

“Additionally, compounded versions of topical cidofovir have been used with some success” (opens the source at this quote in a new tab)

“topical cidofovir use was limited by logistic difficulties, as it requires a compounding specialty pharmacy, and it is not cost-effective for patients with large (i.e., more than a few centimeters) mucocutaneous lesions.” (opens the source at this quote in a new tab)

Foscarnet 1% cream: phase 1/2 open-label trial in AIDS, design

“The efficacy and toxicity of foscarnet cream for the treatment of mucocutaneous herpes simplex virus lesions or lesions that were clinically unresponsive to systemic acyclovir treatment (median, 30.5 days) in AIDS patients were studied in a phase I/II, open-label, nonrandomized multicenter trial.” (opens the source at this quote in a new tab)

“In the study, 20 patients with advanced stages of AIDS were treated with foscarnet 1% cream five times a day for a mean duration of 34.5 days.” (opens the source at this quote in a new tab)

Foscarnet 1% cream: lesion response, viral culture, and pain

“Response of index lesions (n = 20) was judged to be completely healed (8 lesions), excellent (4 lesions), or good (1 lesion) in 65% of lesions.” (opens the source at this quote in a new tab)

“The median time to first negative herpes simplex virus culture of index lesion was 8 days.” (opens the source at this quote in a new tab)

“Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had at least a 50% reduction.” (opens the source at this quote in a new tab)

Foscarnet 1% cream: adverse events and new lesions at untreated sites

“Clinical adverse events included skin ulceration (4 patients), application site reactions (3 patients), fever (3 patients), and headache (3 patients).” (opens the source at this quote in a new tab)

“Five (25%) patients developed new lesions due to herpes simplex virus at sites other than those being treated topically while enrolled in the study.” (opens the source at this quote in a new tab)

Trifluridine 1% ophthalmic solution: open-label pilot study in AIDS, design

“Twenty-six AIDS patients were enrolled in an open label pilot study to evaluate the efficacy and toxicity of topical 1 percent ophthalmic trifluridine solution for the treatment of chronic mucocutaneous herpes simplex virus disease unresponsive to at least 10 days of acyclovir therapy.” (opens the source at this quote in a new tab)

“Twenty-four patients were evaluable for efficacy and 25 for toxicity analyses.” (opens the source at this quote in a new tab)

Trifluridine 1% ophthalmic solution: healing and discontinuation

“Seven patients (29 percent) had complete healing of lesions. The overall estimated median time to complete healing was 7.1 weeks.” (opens the source at this quote in a new tab)

“An additional seven patients had > or = 50 percent reduction in lesion area. The overall estimated median time to 50 percent healing was 2.4 weeks.” (opens the source at this quote in a new tab)

“Ten (42 percent) patients discontinued treatment for reasons other than primary treatment failure and seven (29 percent) for failure to respond to therapy.” (opens the source at this quote in a new tab)

“Baseline patient characteristics associated with greater reduction in lesion area included higher Karnofsky score (p = 0.05), fewer lesions (p = 0.07), smaller lesion area (p = 0.11), and trifluridine susceptibility (p = 0.07).” (opens the source at this quote in a new tab)

Trifluridine 1% ophthalmic solution: toxicity and new lesions outside the treated area

“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)

“No dose-limiting toxicity attributable to trifluridine was reported.” (opens the source at this quote in a new tab)

Trifluorothymidine combined with interferon alfa in three participants with AIDS

“Three AIDS patients with severe cutaneous herpes simplex virus (HSV) infection refractory to therapy with acyclovir and foscarnet (2 patients) were treated with a topical preparation of trifluorothymidine (TFT) and interferon-alpha.” (opens the source at this quote in a new tab)

“Complete healing of lesions occurred in 1 patient; a second had significant regression of the infected area.” (opens the source at this quote in a new tab)

“In the third, the lesion was stabilized twice after application of the preparation and reduced in size after a subsequent treatment.” (opens the source at this quote in a new tab)

Trifluridine ophthalmic solution: labeled adverse reactions and mutagenic potential

“The most frequent adverse reactions reported during controlled clinical trials were mild, transient burning or stinging upon instillation (4.6%) and palpebral edema (2.8%).” (opens the source at this quote in a new tab)

“Trifluridine has been shown to exert mutagenic, DNA-damaging and cell-transforming activities in various standard in vitro test systems, and clastogenic activity in Vicia faba cells.” (opens the source at this quote in a new tab)

Use and duration of topical antivirals in a United States multicenter transplant cohort

“Non-NUCs (second-line therapies) include mainly foscarnet, IV cidofovir, or topical cidofovir and topical imiquimod.” (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)

“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)