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doi: 10.1136/sti.2010.04743115, 2011

2011 87: 292-295 originally published online MarchSex Transm Infect Nicky Perkins, Mitzi Nisbet and Mark Thomas case series and literature reviewaciclovir-resistant herpes simplex disease:Topical imiquimod treatment of

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Topical imiquimod treatment of aciclovir-resistantherpes simplex disease: case series andliterature reviewNicky Perkins,1 Mitzi Nisbet,2 Mark Thomas2

ABSTRACTInfection with herpes simplex virus (HSV) is extremelycommon worldwide. In immunocompromised patientsanogenital HSV disease may have atypical features andmay be very severe. Treatment of aciclovir-resistantanogenital HSV disease is challenging, as resistance toalternative treatments may occur, and effectivetreatment generally involves intravenous therapy withrelatively toxic agents such as foscarnet. This case reportpresents three immunocompromised patients withpresumed aciclovir-resistant anogenital HSV disease whowere successfully treated with topical imiquimod.

Imiquimod promotes local immune activation, whichresults in resolution of viral lesions such as anogenitalwarts and HSV disease. It is convenient to use andavoids the necessity for intravenous treatment withsubstantial systemic toxicity. In addition, as the mode ofaction of imiquimod is related to immune stimulationrather than direct antiviral activity, it may be usedrepeatedly without resistance developing.

Infection with herpes simplex virus (HSV) isextremely common worldwide. Seroprevalencevaries widely between different geographical and

population groups, and is particularly high in HIV-infected individuals, reaching levels over 90% incountries where HIV is endemic. 1 2 In immuno-compromised patients anogenital HSV disease may have atypical features and may be very severe. 3

The main mechanism of HSV resistance isthrough thymidine kinase de ciency. As aciclovirrequires phosphorylation by thymidine kinase inorder to activate, thymidine kinase de ciency confers resistance to aciclovir, as well as to similaragents such as valaciclovir and famciclovir. Occa-sionally HSV strains are also resistant to foscarnetand cidofovir through altered viral DNA poly-merase.4 The most commonly used agents forthe treatment of aciclovir-resistant genital herpesare foscarnet or cidofovir; however, both havesigni cant toxicity and require intravenousadministration.

Strains of HSV resistant to aciclovir were rstisolated in the early 1980s, almost exclusively fromimmunocompromised individuals, with a preva-lence of 5.6% compared with 0.3% in the generalpopulation. The prevalence of aciclovir-resistantHSV has remained stable over 20 years of surveil-lance, despite concerns about the widespread use of aciclovir suppressive therapy for recurrent genitalherpes.4

We report three immunocompromised patientswith presumed aciclovir-resistant anogenital HSV

disease, who were successfully treated with topicalimiquimod.

CASE 1 A 45-year-old HIV-positive woman with knownrecurrent genital HSV disease presented to thesexual health service in September 2004 witha painful vulval lesion of 5 days ’ duration. Threemonths previously her acyclovir suppressive therapy had been reduced from 400 mg twice daily to400 mg daily in view of her low body weight. Shehad commenced antiretroviral treatment withlamivudine 150 mg twice daily, zidovudine 250 mgtwice daily and indinavir 600 mg twice daily in2002 when her CD4 cell count was 27. Since thenher HIV viral load had consistently been unde-tectable ( < 1.7 log10 copies/ml) and her CD4 cellcount had risen to 239 cells/mm 3 at the time of presentation.

Examination revealed a yellow exudative papularlesion of the clitoral hood, which was culturepositive for HSV-2. She was treated with oralaciclovir initially in a dose of 400 mg ve timesdaily for 5 days followed by 800 mg three timesdaily for 4 weeks. Following a positive culture for

Staphylococcus aureus from the lesion, she was alsotreated with ucloxacillin 500 mg three times a day for 4 weeks for presumed bacterial superinfection.The lesion continued to increase in size over thenext 5 weeks and remained HSV-2 culture positive. A biopsy performed to exclude alternative diag-noses showed a sub-acute in ammatory in ltrate,multinucleated epithelial cells consistent with HSVinfection and no evidence of malignancy.

The patient was then admitted to hospital andtreated with aciclovir 500 mg, three times a day for7 days followed by topical cidofovir 1% cream. Thiswas discontinued because she was unable totolerate the associated pain, and the lesionremained culture positive for HSV-2. She wassubsequently admitted again and treated withfoscarnet (1.8 g three times daily) for 21 days andreceived a further 4 days of topical cidofovir1% cream. Following cessation of treatment withfoscarnet the lesions completely healed over thesubsequent 2 weeks and were culture negative forHSV-2 at 20 days and 27 days after starting treat-ment with foscarnet. The episode lasted 4 monthsin total, with complete healing achieved by January 2005.

Subsequently the patient had ve re-admissionsover the next 3 years for culture-positive recur-

rences of genital HSV disease, despite continuedmaintenance therapy with aciclovir 400 mg twice

1 Auckland Regional SexualHealth Service, AucklandDistrict Health Board, Auckland,New Zealand2 Auckland Regional InfectiousDiseases Service, AucklandDistrict Health Board, Auckland,New Zealand

Correspondence toDr Nicky Perkins, AucklandRegional Sexual Health Service,Auckland District Health Board,Private Bag 92024, AucklandMail Centre 1142, Auckland,New Zealand;[email protected]

Accepted 21 February 2011Published Online First15 March 2011

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daily. On each of these occasions she was successfully treatedwith foscarnet (2 g three times daily) for 14 e 42 days; however,it became increasingly dif cult to obtain vascular access andresolution of the lesions was slow, with episodes lasting from 6 to 8 weeks.

In September 2008 she presented with a new recurrence, and

on this occasion was treated with topical imiquimod 5% creamapplied directly to the lesion three times weekly for 3 weeks,with complete resolution ( gures 1A,B). When she againpresented 6 weeks later with a further recurrence, imiquimodthree times weekly was again used, but when minimal responsehad occurred by 3 weeks the frequency of application wasincreased to daily, with subsequent complete resolution in thefollowing week.

Over the following 12 months the patient has had fourfurther episodes all treated successfully with imiquimod. Daily application during the rst episode was found to result in rapidhealing, but caused a severe local reaction, and the three subse-quent episodes have been managed with alternate day applica-tions. Lesions have lasted on average 3e 4 weeks, and the patientis happy with the current treatment regimen as this causes herminimal discomfort and she is able to treat herself at home withonly one or two hospital visits for monitoring. She remains onprophylaxis with aciclovir 400 mg twice daily.

CASE 2 A 78-year-old man with a low grade B-cell lymphoma was treatedwith rituximab, udarabine and mitozantrone for diseaseprogression, having previously been treated 3 years earlier withsix cycles of oral chlorambucil followed by six cycles of R-CVPchemotherapy. Following his fourth cycle of chemotherapy hedeveloped perianal ulceration due to HSV and was treated witha course of oral aciclovir (400 mg, three doses per day) of uncer-tain duration, with a satisfactory clinical response. However, hehad a prolonged recurrence of perianal HSV disease after the nexttwo cycles of chemotherapy and although oral aciclovir treatmentprovided some initial clinical improvement this was not sustainedand he developed chronic perianal ulceration.

Despite several courses of treatment with oral aciclovir (400 mg,ve doses per day) for 10 days over the next 3 months, followed

by treatment with intravenous aciclovir (750 mg 8-hourly) for7 days, the ulcer failed to resolve. A surgical biopsy showedgranulation tissue formation with acute and chronic in amma-tory cellular in ltrates, viral inclusions consistent with HSV andno evidence of dysplasia or malignancy. HSV-2 was cultured fromthe lesions and PCR for HSV DNA was positive.

Methicillin-resistant S aureus and mixed anaerobes including Bacteroides fragilis were repeatedly isolated from ulcer swabs. He

was sequentially treated with intravenous ceftriaxone (2 g daily)and oral metronidazole (400 mg three times a day) for 7 days,oral amoxicillin/clavulanate (625 mg three times a day) for14 days and oral cotrimoxazole (960 mg three times a day) andmetronidazole (400 mg three times a day) for 28 days, with nosymptomatic or clinical bene t.

He was then presumed to have disease caused by aciclovir-resistant HSV and was treated with intravenous foscarnet (2.8 gthree times a day) for 19 days. He had a signi cant clinicalresponse with granulation of the ulcers, and HSV could not beisolated from ulcer swabs collected on day 14 of foscarnettreatment. He was discharged on oral valaciclovir 500 mg twicedaily but had a relapse 2 weeks after the completion of foscarnettreatment ( gure 2).

He was then commenced on alternate day topical imiquimod. After 6 weeks of treatment with imiquimod he had a markedclinical improvement, with granulation tissue covering over 50%of the previously ulcerated areas. Over the following months hehad persisting ulceration but this was controlled with alternateday topical imiquimod. He did not require further hospitaladmission for the management of perianal HSV disease until4 months after commencing topical imiquimod, when he wasadmitted with transformed diffuse B-cell lymphoma. He diedfrom lymphoma 9 days after admission.

CASE 3 A 42-year-old man with HIV infection, who had commencedantiretroviral treatment with tenofovir 300 mg daily, emtricita-bine 200 mg daily and efavirenz 600 mg daily 3 months previ-ously, following a CD4 cell count nadir of 170 cells/mm 3 (8%),

Figure 1 (A) Genital herpes lesionbefore treatment. (B) Re-epithelialisationafter 14 days treatment with imiquimod.

Figure 2 Papular perianal genital herpes lesions before treatment.

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presented with a non-tender penile ulcer with associated inguinallymphadenopathy. HSV disease was con rmed by PCR of anulcer swab. At the time of presentation his CD4 cell count was654 cells/mm 3 (16%) and his viral load was 1.8 log10 copies/ml.Despite treatment with oral aciclovir (400 mg three times a day)for 32 days followed by treatment with intravenous aciclovir(500 mg three times a day) for 7 days the ulcer failed to resolve.

The patient declined treatment with intravenous foscarnetdue to concerns about the potential side effects. He waspresumed to have aciclovir-resistant HSV disease and wascommenced on topical imiquimod three times per week, andcontinued prophylaxis with oral aciclovir (400 mg twice daily).

The patient was initially reluctant to apply imiquimod and

only used it on a very infrequent basis. During this period theulcer continued to deteriorate and increased to 1 cm by 1 cm insize. The patient was again encouraged to apply topicalimiquimod every second day, which he did for 3 weeks duringwhich time the ulcer healed completely. The patient remains onprophylactic oral aciclovir (400 mg twice daily), and has had twofurther recurrences of genital HSV disease, both successfully treated with topical imiquimod.

DISCUSSIONThe three patients we have reported provide evidence thatimiquimod may be an effective treatment for patients withpresumed aciclovir-resistant anogenital HSV disease. We do nothave access to testing of HSV either for inhibition of in-vitroreplication in the presence of aciclovir, or for the presenceof mutations in thymidine kinase or DNA polymerase genesthat are most frequently associated with in-vitro and in-vivoaciclovir resistance. Therefore, a presumptive diagnosis of aciclovir-resistant anogenital HSV disease in our patients wasmade on the basis of lack of clinical response to prolongedtreatment with intravenous aciclovir given in high dosestogether with the repeated isolation of HSV-2 while on suchtreatment. This approach is consistent with the British Associ-ation for Sexual Health and HIV (BASHH) clinical effectivenessguidelines 2007.5

Imiquimod is an imidazoquinoline, and has a mechanism of action thought to be through stimulation of Toll-like receptor 7.

This causes activation of monocytes, macrophages and dendriticcells and secretion of pro-in ammatory cytokines. In addition,

imiquimod stimulates other cell-mediated immune responsesresulting in the production of IFN g , TNFa and IL-12. This localimmune activation results in the resolution of viral lesions suchas anogenital warts and HSV disease. 6 The advantages of imiquimod as an option for the treatment of aciclovir-resistantHSV include the ability for the patient to apply treatment athome, lack of systemic toxicity and lack of potential for thedevelopment of resistance because imiquimod is an immunestimulator rather that a direct antiviral agent.

Much of the evidence for the use of imiquimod in the treat-ment of anogenital HSV disease comes from early studies on theguinea pig model. These data indicated reduced numbers of lesions, viral shedding and viral content in the spinal cord

following the application of imiquimod. In addition, there werereduced numbers of recurrences following treatment. 7 8 Humandata are scarce, and imiquimod is not routinely used in thetreatment of anogenital HSV disease as a result of the easy availability of other agents. We found nine reports describingsuccessful treatment with imiquimod for aciclovir-resistant HSVdisease in immunocompromised individuals (table 1). 9 e 16

Sensitivity testing was performed in ve of the nine cases andin three of these the HSV isolate was shown to have an inhib-itory concentration of aciclovir greater than 2 mg/ml. 11 15 In theother two cases the isolate was sensitive to aciclovir but therewas no clinical response to treatment. 14 16 The most commonly used imiquimod regimen was three times weekly application,and all reported full resolution of lesions with no report of any

associated adverse effects. Seven case reports included data onfollow-up, and of these only two reported recurrences, both of which were managed successfully with imiquimod. The use of an ongoing prophylactic regimen was recorded in three casereports.

In summary, imiquimod may a useful adjunct in the treat-ment of presumed aciclovir-resistant anogenital HSV disease. Itis convenient to use and avoids the necessity for intravenoustreatment with substantial systemic toxicity. In addition, as themode of action of imiquimod is related to immune stimulationrather than direct antiviral activity, it may be used repeatedly without the likelihood of the development of resistance.

Competing interests None declared.

Patient consent Obtained.

Table 1 Summary of case reports of imiquimod for the treatment of aciclovir-resistant herpes simplex infection

AuthorAge(years) Sex

HSVtype

Medicalcondition

Imiquimodregimen

Time tohealing Follow-up Recurrences Prophylaxis

Lautenschlager et al 9 46 M HSV-2 HIV 33 Week 5 Weeks Yes timenot noted

Several managedwith imiquimod

Not documented

Gilbert et al 10 34 M HSV-2 HIV 33 Week 1 Week 1 Month None Not documentedMartinez et al 11 37 M HSV-2 HIV 33 Week

(stopped after2 weeks)

4 Weeks 12 Months None No

31 M HSV-1 Lymphocyticleukaemia(Note: non-genital)

43 Daily 4weeks then dailyfor 3 months

4 Weeks 10 Months None Valaciclovir

Yudin and Kaul12 34 F HSV-2 HIV 33 Week 8 Weeks 21 Months None Valaciclovirimiquimod(fortnightly)

Abbo et al 13 42 M HSV-2 HIV 33 Week 2 Weeks NoneDanielson et al 14 28 M HSV-1 HIV Not documented 10 Weeks 20 Months None FamciclovirBrummit15 72 F HSV-2 Rheumatoid arthritis

(methotrexate)33 Week 10 Weeks 9 Months One managed

with sameregimen

Not documented

Bangsgaardand Skov16

79 F HSV-2 Lymphaticleukaemia

33 Weekthen daily

14 Weeks None

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Contributors NP: desciption of case 1 and preparation of the manuscript; MN andMT: description of cases 2 and 3 and revision of the manuscript.

Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES1. Malkin JE. Epidemiology of genital herpes simplex virus infection in developed

countries. Herpes 2004;11(Suppl 1):2e 23A.2. Weiss H. Epidemiology of herpes simplex virus type 2 infection in developing

countries. Herpes 2004;11(Suppl 1):24e 35A.3. Strick L, Wald A, Celum C. Management of herpes simplex virus type 2 infection in

HIV type 1 infected persons. Clin Infect Dis 2006;43:347e 56.4. Bacon T, Levin M, Leary J, et al . Herpes simplex virus resistance to acyclovir and

penciclovir after two decades of antiviral therapy. Clin Microbiol Rev 2003;16:114e 28.5. British Association for Sexual Health and HIV (BASHH). Clinical effectiveness

group guidelines. http://www.bashh.org/guidelines (accessed 17 Sep 2010).6. Hengge U, Benninghoff B, Ruzicka T, et al . Topical immunomodulatorsd progress

towards treating inammation,infectionand cancer. Lancet Infect Dis2001;1:189e 98.7. Harrison CJ, Miller RL, Bernstein DI. Posttherapy suppression of genital

herpes simplex virus (HSV) recurrences and enhancement of HSV-specic T-cellmemory by imiquimod in guinea pigs. Antimicrob Agents Chemother 1994;38:2059e 64.

8. Bernstein DI, Harrison CJ, Tomai MA, et al . Daily or weekly therapy withresimiquimod (R-848) reduces genital recurrences in herpes simplex virus-infected guinea pigs during and after treatment. J Infect Dis 2001;183:844e 9.

9. Lautenschlager S, Schwarzkopf S, Keller B. Exophytic ulcerated tumors in HIVpatients: diagnostic and therapeutic problems. Dermatology 2008;216:60e 3.

10. Gilbert J, Drehs M, Weinberg J, et al . Topical imiquimod for acyclovir-unresponsiveherpes simplex virus 2 infection. Arch Dermatol 2001;137:1015e 17.

11. Martinez V, Molina JM, Scieux C, et al . Topical imiquimod for recurrent aciclovir-resistant HSV infection. Am J Med 2006;119:e9e 11.

12. Yudin M, Kaul R. Progressive hypertrophic genital herpes in an HIV-infected womandespite immune recovery on antiretroviral therapy. Infect Dis Obstet Gynecol 2008;2008:592532.

13. Abbo L, Vincek V, Dickinson G, et al . Selective defect in plasmacytoid dendritic cellfunction in a patient with AIDS-associated atypical genital herpes simplex vegetanstreated with imiquimod. Clin Infect Dis 2007;44:e25e 7.

14. Danielson AG, Petersen CS, Iverson J. Chronic erosive herpes simplex virusinfection of the penis in a human immunodeciency virus-positive man, treated withimiquimod and famciclovir. Br J Dermatol 2002;147:1034e 5.

15. Brummit CF. Imiquimod 5% cream for the treatment of recurrent acyclovir-resistantgenital herpes. Clin Infect Dis 2006;42:575.

16. Bangsgaard N, Skov L. Chronic genital ulceration due to herpes simplex infectiontreated successfully with imiquimod. Acta Derm Venereol 2008;88:202e 3.

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