National Institutes of Health opportunistic infections guideline: imiquimod 5% cream as an alternative therapy rated BIII

“Topical imiquimod 5% cream three times a week (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)
“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)

Centers for Disease Control and Prevention sexually transmitted infections guideline: imiquimod 5% as an alternative for acyclovir-resistant genital herpes

“Imiquimod 5% applied to the lesion for 8 hours 3 times/week until clinical resolution is an alternative that has been reported to be effective” (opens the source at this quote in a new tab)

European genital herpes guideline: immunomodulators for hypertrophic herpes simplex

“Hypertrophic herpes simplex is an unusual condition often presenting with painful and exophytic tumoral nodules with or without an ulcerated surface located predominantly in the anogenital region.” (opens the source at this quote in a new tab)
“It is often refractory to first‐line systemic antiviral agents such as aciclovir (administered orally or intravenously), valaciclovir and famciclovir; a higher frequency of drug‐resistant HSV strains has been described.” (opens the source at this quote in a new tab)
“Immunomodulators, such as topical imiquimod, or thalidomide, can be useful in treating this condition.” (opens the source at this quote in a new tab)

Labeled indications of imiquimod 5% cream

“ALDARA is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) on the face or scalp in immunocompetent adults.” (opens the source at this quote in a new tab)
“ALDARA is indicated for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, with a maximum tumor diameter of 2.0 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured.” (opens the source at this quote in a new tab)
“ALDARA is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.” (opens the source at this quote in a new tab)
“ALDARA is for topical use only. ALDARA is not for oral, ophthalmic, or intravaginal use.” (opens the source at this quote in a new tab)

Off-label status, dose, and monitoring of imiquimod 5% as tabulated in a review

Field	Quoted entry
Mechanism of action	“Toll-like receptor 7 agonist that activates immune cells”
Dose	“Three times a week”
Clinically significant adverse reactions	“Dermatologic: localized erythema, xeroderma, crusted skin, and dermal ulcer”“Systemic and flu-like reactions.”
Monitoring	“Local reaction”
FDA approval or off-label use	“Off-label use”

Licensed use and proposed basis for use in refractory genital ulcers

“Imiquimod is used for external anogenital warts, superficial basal cell carcinoma, and actinic keratoses treatment” (opens the source at this quote in a new tab)
“Its antiproliferative action may contribute to its effectiveness in treating R/R HSV genital ulcers” (opens the source at this quote in a new tab)
“Imiquimod use has been described in a case series of HCT recipients, often as part of a combination regimen, for patients with genital and/or perianal lesions in particular” (opens the source at this quote in a new tab)

Clinical trials of imiquimod in herpes labialis and genital herpes as summarized in a review

“A topical formulation of imiquimod is licensed for the treatment of genital and perianal warts caused by human papillomavirus” (opens the source at this quote in a new tab)
“Topical application of imiquimod and resiquimod showed contradictory results in clinical trials evaluating their efficacy in the treatment of herpes labialis” (opens the source at this quote in a new tab)
“and genital herpes” (opens the source at this quote in a new tab)

Systematic review and individual-patient meta-analysis of imiquimod for hypertrophic herpes simplex

“Twenty-five studies (21 case reports and four case series) with a combined total of 42 patients were included.” (opens the source at this quote in a new tab)
“The complete cure rate for imiquimod treatment was estimated at 88.1%.” (opens the source at this quote in a new tab)
“The median time to complete response was 60 days (95% confidence interval 35-70).” (opens the source at this quote in a new tab)
“Combined treatment, male sex, and an age less than 50 years were identified as significant prognostic factors for a shorter time to complete cure.” (opens the source at this quote in a new tab)
“Patients who were male or younger than 50 years or whose treatments were combined with thymidine kinase-dependent antivirals had the best prognoses and were more likely to respond to treatment.” (opens the source at this quote in a new tab)

Case series in HIV infection with herpes simplex virus type 2 resistant to aciclovir and foscarnet

“Four cases of patients infected with HIV and with mucocutaneous HSV-2 resistant to ACV and FOS are reported.” (opens the source at this quote in a new tab)
“These patients were treated successfully with topical 5% imiquimod.” (opens the source at this quote in a new tab)
“Imiquimod treatment also appeared to delay the time to recurrence of HSV lesions.” (opens the source at this quote in a new tab)

Case series of pseudotumoral anogenital herpes in HIV infection treated with immunomodulators

“Between 2003 and 2011, 10 HIV-1-infected patients presenting with chronic pseudotumoral anogenital herpes simplex type 2 (HSV-2) infections were studied.” (opens the source at this quote in a new tab)
“Detection of HSV-2 by culture and/or polymerase chain reaction was positive for all patients, with evidence for ACV-resistant strains in 6 of 8 cases.” (opens the source at this quote in a new tab)
“Durable control was observed with HSV DNA polymerase inhibitors in only 2 cases, and the immunomodulators imiquimod and thalidomide allowed 5 patients to reach sustained complete response.” (opens the source at this quote in a new tab)

Case series of three immunocompromised participants with presumed aciclovir-resistant anogenital disease

“This case report presents three immunocompromised patients with presumed aciclovir-resistant anogenital HSV disease who were successfully treated with topical imiquimod.” (opens the source at this quote in a new tab)
“It is convenient to use and avoids the necessity for intravenous treatment with substantial systemic toxicity.” (opens the source at this quote in a new tab)
“In addition, as the mode of action of imiquimod is related to immune stimulation rather than direct antiviral activity, it may be used repeatedly without resistance developing.” (opens the source at this quote in a new tab)

Case report in HIV infection after failure of oral antivirals

“We present a case of a human immunodeficiency virus (HIV)-positive patient who was successfully treated with topical imiquimod after treatment failures with other oral antivirals.” (opens the source at this quote in a new tab)

Adjunctive imiquimod in people living with HIV in a French case series

“Among PLHIV, infections included recurrent genital herpes and atypical pseudo-tumoral lesions, managed with foscarnet or adjunctive topical cidofovir or imiquimod.” (opens the source at this quote in a new tab)
“Several alternative therapies were introduced, including topical cidofovir and imiquimod, prolonged VACV therapy (6 weeks), and pritelivir.” (opens the source at this quote in a new tab)
“However, all treatment attempts resulted in only partial clinical responses, and the herpetic lesions persisted.” (opens the source at this quote in a new tab)
“At that time the patient was treated with VACV 1 gram twice daily, resulting in significant clinical improvement and regression of the lesion, after adjunction of topical imiquimod.” (opens the source at this quote in a new tab)
“Complete healing was achieved, and no recurrences were observed over a one-year follow-up period under VACV prophylaxis.” (opens the source at this quote in a new tab)

Combination use with intravenous foscarnet in allogeneic transplant recipients

“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)

Reports of topical imiquimod in transplant recipients as tabulated in a review

Report	Topical regimen	Systemic concurrent therapy	Topical treatment adverse effects	Outcome
One recipient with genital and buttock HSV-2 infection (2021 report)	“Imiquimod 5% cream”	“None”	“It was not specified, but it resulted in treatment cessation.”	“Imiquimod was not tolerated after a week of use.”
Three of 18 recipients (2018 cohort)	“Imiquimod 5% cream”	“i.v. FOS, oral VACV, or i.v. CDV”	“AKI (concurrent i.v. FOS or CDV)”	“Unspecified”

Absence of clinical trials supporting topical therapy added to systemic treatment

“Topical therapy with CDV or imiquimod cream has been used in addition to systemic treatment for R/R HSV infections despite no supporting clinical trials.” (opens the source at this quote in a new tab)

Label warnings: local skin reactions and inflammatory skin conditions

“Local skin reactions including skin weeping or erosion have been reported with ALDARA and can occur after a few applications” (opens the source at this quote in a new tab)
“ALDARA has the potential to exacerbate inflammatory conditions of the skin, including chronic graft versus host disease.” (opens the source at this quote in a new tab)
“Severe local inflammatory reactions of the female external genitalia can lead to severe vulvar swelling and urinary retention.” (opens the source at this quote in a new tab)
“Avoid application of ALDARA to skin that is not intact (i.e., any area with an abrasion, cut, burn, rash, infection, or other condition that has altered skin integrity).” (opens the source at this quote in a new tab)

Label warnings: hypopigmentation and systemic reactions

“Cases of hypopigmentation, including complete depigmentation, were reported during postmarketing use of ALDARA.” (opens the source at this quote in a new tab)
“Flu-like signs and symptoms have been reported with use of ALDARA and may accompany, or even precede, local inflammatory reactions” (opens the source at this quote in a new tab)
“Signs and symptoms may include malaise, fever, nausea, myalgias, and rigors.” (opens the source at this quote in a new tab)

Local skin reactions in vehicle-controlled trials of imiquimod 5% cream for external genital warts

Reaction	Imiquimod, females (n=114), all grades	Imiquimod, females, severe	Imiquimod, males (n=156), all grades	Imiquimod, males, severe	Vehicle, females (n=99), all grades	Vehicle, females, severe	Vehicle, males (n=157), all grades	Vehicle, males, severe
Erythema	“74 (65%)”	“4 (4%)”	“90 (58%)”	“6 (4%)”	“21 (21%)”	“0 (0%)”	“34 (22%)”	“0 (0%)”
Erosion	“35 (31%)”	“1 (1%)”	“47 (30%)”	“2 (1%)”	“8 (8%)”	“0 (0%)”	“10 (6%)”	“0 (0%)”
Excoriation or flaking	“21 (18%)”	“0 (0%)”	“40 (26%)”	“1 (1%)”	“8 (8%)”	“0 (0%)”	“12 (8%)”	“0 (0%)”
Edema	“20 (18%)”	“1 (1%)”	“19 (12%)”	“0 (0%)”	“5 (5%)”	“0 (0%)”	“1 (1%)”	“0 (0%)”
Scabbing	“4 (4%)”	“0 (0%)”	“20 (13%)”	“0 (0%)”	“0 (0%)”	“0 (0%)”	“4 (3%)”	“0 (0%)”
Induration	“6 (5%)”	“0 (0%)”	“11 (7%)”	“0 (0%)”	“2 (2%)”	“0 (0%)”	“3 (2%)”	“0 (0%)”
Ulceration	“9 (8%)”	“3 (3%)”	“7 (4%)”	“0 (0%)”	“1 (1%)”	“0 (0%)”	“1 (1%)”	“0 (0%)”
Vesicles	“3 (3%)”	“0 (0%)”	“3 (2%)”	“0 (0%)”	“0 (0%)”	“0 (0%)”	“0 (0%)”	“0 (0%)”

Selected adverse reactions in vehicle-controlled trials of imiquimod 5% cream for external genital warts

Adverse reaction	Imiquimod, females (n=117)	Vehicle, females (n=103)	Imiquimod, males (n=156)	Vehicle, males (n=158)
Wart site itching	“38 (32%)”	“21 (20%)”	“34 (22%)”	“16 (10%)”
Wart site burning	“30 (26%)”	“12 (12%)”	“14 (9%)”	“8 (5%)”
Wart site pain	“9 (8%)”	“2 (2%)”	“3 (2%)”	“1 (1%)”
Wart site soreness	“3 (3%)”	“0 (0%)”	“0 (0%)”	“1 (1%)”
Fungal infection	“13 (11%)”	“3 (3%)”	“3 (2%)”	“1 (1%)”
Headache	“5 (4%)”	“3 (3%)”	“8 (5%)”	“3 (2%)”
Influenza-like symptoms	“4 (3%)”	“2 (2%)”	“2 (1%)”	“0 (0%)”
Myalgia	“1 (1%)”	“0 (0%)”	“2 (1%)”	“1 (1%)”

Discontinuation for local reactions in the genital wart trials

“The most frequently reported adverse reactions were local skin and application site reactions. Overall, 1.2% (4/327) of the subjects discontinued treatment due to local skin/application site reactions.” (opens the source at this quote in a new tab)

Severe local reaction rate in the meta-analysis of hypertrophic herpes simplex

“A severe local reaction was reported in 2.3%.” (opens the source at this quote in a new tab)

Tolerability in a single-center series of allogeneic transplant recipients

“In our experience, topical imiquimod was not well tolerated, as the patient experienced local irritation with discomfort after application, and 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)