Recalcitrant Giant Molluscum Contagiosum in a Patient With ...

Case Report from the Field Volume 18 Issue 5 December 2010Case Report From the FieldRecalcitrant Giant Molluscum Contagiosum in a PatientWith Advanced HIV Disease — Eradication of Disease WithPaclitaxelSilver Cree Sisneros, DOBackgroundMolluscum contagiosum is a poxvirusskin infection that is self-limitedand harmless, usually causing numeroussingle, umbilicated papules in immunocompetentpeople. However, apatient with immunodeficiency suchas that associated with HIV diseasemay present with giant, widespread,and chronic lesions, for which nosingle intervention has been shownto be convincingly effective for curativetreatment. Poxviruses utilize themicrotubule cytoskeleton within thecytoplasm of eukaryotic cells for movementinto the human host cell duringthe establishment of infection and forfacilitating the continued spread of virusinfection. Paclitaxel, a chemotherapeuticdrug used for treatment of cancer,targets the host cell’s microtubulecytoskeleton, resulting in apoptoticprogrammed cell death and potentialdisruption of the molluscum contagiosumvirus (MCV) lifecycle. This, in turn,potentially leads to decreased viralreplication and ultimately decreasedburden of disease. We report here anunusual case of giant molluscum contagiosumlesions in a person with AIDS,refractory to conventional therapy butresponsive to treatment with paclitaxel.No similar case appears to havebeen described previously.Case PresentationA 25-year-old, HIV-infected, heterosexualman from Mexico presented foran initial consult, reporting a 12-monthhistory of extensive groin and faciallesions. The lesions had worseneddespite the initiation of antiretroviraltreatment 3 months earlier. At the timeantiretroviral therapy was initiated, thepatient’s CD4+ cell count was 23/µLand plasma HIV RNA level was 32,640copies/mL. His antiretroviral treatmentconsisted of atazanavir 300 mg daily,ritonavir 100 mg daily, and fixed-dosecombination emtricitabine/tenofovir200 mg/300 mg daily. Additional medicationsincluded fixed-dose combinationtrimethoprim/sulfamethoxazole800 mg/160 mg daily and clarithromycin500 mg twice daily, for prophylaxisof Pneumocystis pneumonia and disseminatedMycobacterium avium complexdisease, respectively. On initialpresentation to the clinic, 3 months afterstarting antiretroviral treatment, hisCD4+ cell count was 59/µL and plasmaHIV RNA level was 337 copies/mL.Initial examination revealed large papules,nodules, and plaques,some of which were extensive,ulcerating lesions,predominantly affecting thegroin area and bilateralthighs, with perinodularscarring, evidence of bleeding,and hyperpigmentation.The lesions rangedin diameter from 4 mm to20 mm, were quite tenderto palpation, and causedtremendous pain duringambulation (Figure 1). Numerousfacial lesions werealso present that rangedin diameter from 3 mm to5 mm. Biopsy specimensfrom 2 thigh lesions revealedpositive pathology for MCV infection,with characteristic histologicfeatures of large, eosinophilic, intracytoplasmicinclusion bodies (Figure 2).Therapeutic ChallengeIn patients with advanced HIV disease,molluscum contagiosum can presentas an opportunistic infection and causewidespread, giant lesions that are particularlyresistant to therapy. 1,2 Antiretroviraltherapy may result in reconstitutionof the host’s immunity and mayassist with resolution or improvementof MCV lesions, but success may be difficultto achieve. Historical treatmentapproaches, such as excision, topicaltreatment, and cryotherapy, are oftenminimally effective for treatment of extensiveand severe disease.Initial treatment with continued antiretroviraltherapy in addition to topi-Figure 1. Lesions in the groin and thigh areas on presentationof a 25-year-old, HIV-seropositive man with molluscumcontagiosum virus infection. Extensive, ulceratinglesions were accompanied by perinodular scarring, signsof bleeding, and hyperpigmentation.Dr Sisneros is a physician with a private practice in internal medicine in Marietta, Ohio.Send correspondence to Silver Cree Sisneros, DO, at DrSisneros@live.com. Received August 26, 2010; accepted November 23, 2010.169

International AIDS Society–USATopics in HIV MedicineNormalKeratinocyteHypergranulosisMolluscum Body(Henderson-Patterson Body)Figure 2. A section of a biopsy specimen from a thigh lesion revealinghistologic features characteristic of infection with molluscumcontagiosum virus: large, eosinophilic, intracytoplasmic inclusionbodies (Henderson-Patterson bodies).cal liquid nitrogen cryotherapy was notassociated with any improvement inthis patient’s lesions. Considerationwas given to using topical therapy withimiquimod or cidofovir, but because ofthe extent of the lesions, further topicaltreatment was expected to offer nobenefit. The decision was made to useintravenous paclitaxel because of thedrug’s potential ability to alter the lifecycleof the MCV via disruption of thehost’s cellular microtubule cytoskeletonkinetics.The patient was administered “offlabel”treatment (ie, not approved bythe US Food and Drug Administration[FDA]) with intravenous paclitaxel100 mg/m 2 (108 mg), which is a lowerdose than that recommended forthe treatment of ovarian, breast, ornon–small cell lung cancer. This dose(100 mg/m 2 ) has been used successfullyfor the treatment of AIDS-relatedKaposi sarcoma. There are no knowndrug-drug interactions between thepatient’s antiretroviral drugs and paclitaxel.Paclitaxel was administered intravenouslyon an outpatient basis every21 days for 4 cycles of therapy, alongwith standard pretreatment with famotidine,dexamethasone, and diphenhydramine.Within 15 days of receivingthe first injection, the patient experiencedrapid and complete resolution ofall skin lesions, despite persistent immunesuppression(Figure 3).The patient continuedwith the 4scheduled cycles ofchemotherapy withoutany complicationsand remainedfree of MCV diseaseat his last visit,7 months after theinitial consultation(Figure 4). Completeresolution of molluscumcontagiosumpersisted despite thepatient’s nonadherencewith his antiretroviraltherapyand an increase inhis plasma HIV RNAlevel to 10,600 copies/mL.The CD4+ cell count at the lastfollow-up visit was 145/µL.DiscussionMCV was first described in the medicalliterature in 1817 3 and in 1905,molluscum contagiosum was foundto be caused by a large DNA poxvirus(reviewed in reference 3 ). A majorbreakthrough came in 1996, whenthe genome of this tumorigenic viruswas sequenced. 4 With the eradicationof smallpox, MCV is now the onlymember of the poxvirus family thatcurrently causes substantial disease inhumans. 5The study of MCV has been hamperedby the inability to grow this virusin the laboratory and the lack of ananimal model to study theinfection. Vaccinia virus hastherefore become the laboratoryprototype and moststudiedDNA poxvirus, andour knowledge of poxvirusbiology is derived largelyfrom studies of this virus. 6These studies show thatpoxviruses utilize the microtubulecytoskeleton withinthe cytoplasm of eukaryoticcells for movement into thehuman host cell during establishmentof infection andfor facilitating the continued170spread of virus infection. 7-9 Microtubulesare protein-based structural componentsof the host cell cytoskeletonand are involved in maintaining cellshape, intracellular transport, and cellsignaling, along with cell movement,reproduction, and division.Infection with MCV has a worldwideincidence of as much as 8%. 10 Up to18% of patients with HIV infection havesymptomatic molluscum contagiosum,an incidence that increases to 33% forpatients with CD4+ cell counts lessthan 100/µL. 11 In the United States from1990 to 1999, the estimated numberof physician visits for MCV infectionwas 280,000 per year. 12 Acquisition ofthe virus follows contact with infectedpersons or contaminated objectsand sources such as towels, sponges,swimming pools, public baths, tattooinstruments, gymnasium equipment,instruments used in beauty salons, andpublic benches. 3,11,13 The estimated incubationperiod ranges from 14 daysto 6 months. 14 Three distinct diseasepatterns are observed in 3 differentpatient populations: children who aregenerally healthy; adults who are generallyhealthy; and immunocompromisedchildren and adults. 11MCV infection is most common inchildren who become infected eitherdirectly through skin-to-skin contactor indirectly through skin contact withcontaminated objects. In adults, MCVinfection is considered primarily asexually transmitted disease. In immunocompetentchildren and adults, MCVinfection is a harmless, self-limiteddisease that produces a papular erup-Figure 3. Photograph of the patient 15 days after the firstadministration of intravenous paclitaxel, showing resolutionof all skin lesions.

Case Report from the Field Volume 18 Issue 5 December 2010Figure 4. Photograph of the patient 4 months after thefirst administration of paclitaxel, showing sustainedresolution of disease despite the patient’s nonadherenceto his antiretroviral regimen.tion of numerous benign, umbilicatedtumors. 14 The individual tumors aresmall, skin colored, firm, smooth, andpainless, and they have a central whitecaseous plug. Individual lesions healspontaneously and are seldom presentlonger than 2 months. 11 In patients whoare severely immumocompromised orhave advanced HIV disease and lowCD4+ cell counts, the tumors may becomea widespread, chronic opportunisticinfection 2,15 characterized by giant,nodular, 1 necrotic, 16 symptomatic,and disfiguring lesions, with secondaryinfection. 17 In these patients, theimpaired cell-mediated immunity caninterfere with the resolution of diseaseand the tumors may be very resistantto therapy. 18 In immunocompromisedpatients, the differential diagnosis ofMCV disease is important to consider;it can include atypical mycobacterialinfection, cryptococcosis, pyogenicgranuloma, basal cell carcinoma, histoplasmosis,penicillinosis, pneumocystosis,and keratoacanthoma. 19Little data exist with regard to thebest treatment of MCV infection. Nosingle intervention has been shown tobe convincingly effective, and no reliableevidence-based recommendationsexist. 14In healthy adults and children, treatmentis not necessary for recovery, andawaiting spontaneous resolution is apotential management strategy. Treatment,when used, is intended to hastenthis process. Three broad categories oftreatment options have been used historicallyfor MCV disease: physical destructionof the tumor, topicaltreatment, and systemic treatment.Cryotherapy, curettage,and evisceration are examplesof destructive therapy. Treatmentmay be painful and resultin scarring. 14 Topical treatmentsinclude cantharidin,potassium hydroxide, podophyllotoxin,tretinoin, liquefiedphenol, imiquimod, and cidofovir.Systemic treatments thathave been tried include cidofovirand cimetidine. 14,20Traditional antiviral drugsare directed against the proteinsand functional pathwaysof the virus itself. Because poxvirusesrely on cellular pathways to propagate,another possible antiviral treatmentapproach is to direct treatment thatinterferes with the viral functions thatare dependent on the functional machineryof the cell. 21 The microtubulecytoskeleton pathway plays a role inthe lifecycle of poxviruses 7 and maythus represent a new target for poxvirustherapy. 21Paclitaxel targets the host cell’s microtubulecytoskeleton. The drug wasdiscovered in 1964 and is derived fromthe bark of the Pacific yew tree (Taxusbrevifolia). Paclitaxel is approved by theUS FDA as a chemotherapeutic drug forthe treatment of ovarian cancer, breastcancer, non–small cell lung cancer,prostate cancer, and AIDS-related Kaposisarcoma. 22 It belongs to the classof drugs called taxanes, which are anticancerdrugs that have validated theconcept of microtubules as effectivecancer chemotherapeutic targets. 23Cells treated with paclitaxel producetoo many microtubules and as a resultare unable to coordinate cell division;they die after continued attempts toreplicate their DNA without the abilityto divide. 24The rapid clearance of disease inthis case supports the possibility thattreatment with intravenous paclitaxelmight disrupt the MCV lifecycle, therebyresulting in decreased viral replicationand ultimately, decreased burdenof disease. Further clinical studies arerecommended to fully characterize thenature of this response.Financial Disclosure: Dr Sisneros has servedas a scientific advisor and paid lecturer forGilead Sciences, Inc.References1. Vozmediano JM, Manrique A, PetragliaS, Romero MA, Nieto I. Giant molluscumcontagiosum in AIDS. Int J Dermatol.1996;35:45-47.2. Gona P, Van Dyke RB, Williams PL, et al.Incidence of opportunistic and other infectionsin HIV-infected children in the HAARTera. JAMA. 2006;296:292-300.3. Kauffman CL and Beatty CN. Molluscumcontagiosum. eMedicine Dermatology Website. July 23, 2010. http://emedicine.medscape.com/article/1132908-overview. Updated July23, 2010. Accessed November 29, 2010.4. Senkevich TG, Bugert JJ, Sisler JR, KooninEV, Darai G, Moss B. Genome sequence of ahuman tumorigenic poxvirus: prediction ofspecific host response-evasion genes. Science.1996;273:813-816.5. Krathwohl MD, Hromas R, Brown DR,Broxmeyer HE, Fife KH. Functional characterizationof the C---C chemokine-like moleculesencoded by molluscum contagiosumvirus types 1 and 2. Proc Natl Acad Sci U S A.1997;94:9875-9880.6. Harrison SC, Alberts B, Ehrenfeld E, et al.Discovery of antivirals against smallpox. ProcNatl Acad Sci U S A. 2004;101:11178-11192.7. Ploubidou A, Moreau V, Ashman K, ReckmannI, González C, Way M. Vaccinia virus infectiondisrupts microtubule organization and centrosomefunction. EMBO J. 2000;19:3932-3944.8. Hollinshead M, Rodger G, Van Eijl H, etal. Vaccinia virus utilizes microtubules formovement to the cell surface. J Cell Biol.2001;154:389-402.9. Laliberte JP, Moss B. Lipid membranes inpoxvirus replication. Viruses. 2010;2:972-986.10. Billstein SA, Mattaliano VJ, Jr. The "nuisance"sexually transmitted diseases: molluscumcontagiosum, scabies, and crab lice. MedClin North Am. 1990;74:1487-1505.11. Crowe MA. Molluscum contagiosum. eMedicinePediatrics Web site. 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International AIDS Society–USATopics in HIV Medicine13. Postlethwaite R. Molluscum contagiosum.Arch Environ Health. 1970;21:432-452.14. van der Wouden JC, van der Sande R,van Suijlekom-Smit LWA, Berger M, Butler C,Koning S. Interventions for cutaneous molluscumcontagiosum. Cochrane DatabaseSyst Rev. 2009;CD004767.15. Schwartz JJ, Myskowski PL. Molluscumcontagiosum in patients with human immunodeficiencyvirus infection. A review oftwenty-seven patients. J Am Acad Dermatol.1992;27:583-588.16. Baxter KF, Highet AS. Topical cidofovirand cryotherapy--combination treatment forrecalcitrant molluscum contagiosum in a patientwith HIV infection. J Eur Acad DermatolVenereol. 2004;18:230-231.17. Lin HY, Linn G, Liu CB, Chen CJ, Yu KJ.An immunocompromised woman with severemolluscum contagiosum that respondedwell to topical imiquimod: a case reportand literature review. J Low Genit Tract Dis.2010;14:134-135.18. Hivnor C, Shepard JW, Shapiro MS, VittorioCC. Intravenous cidofovir for recalcitrantverruca vulgaris in the setting of HIV. ArchDermatol. 2004;140:13-14.19. Hogan MT. Cutaneous infections associatedwith HIV/AIDS. Dermatol Clin.2006;24:473-95, vi.20. Meadows KP, Tyring SK, Pavia AT, RallisTM. Resolution of recalcitrant molluscumcontagiosum virus lesions in humanimmunodeficiency virus-infected patientstreated with cidofovir. Arch Dermatol.1997;133:987-990.21. Yang H, Kim SK, Kim M, et al. Antiviralchemotherapy facilitates control ofpoxvirus infections through inhibition ofcellular signal transduction. J Clin Invest.2005;115:379-387.22. McEvoy GK, Miller J, Litvak K, eds. AHFSDrug Information 2004. Bethesda, MD: AmericanSociety of Health-System Pharmacists;2004:1100-1111.23. Zhou J, Giannakakou P. Targeting microtubulesfor cancer chemotherapy. Curr MedChem Anticancer Agents. 2005;5:65-71.24. The discovery of camptothecin and Taxol®.American Chemical Society. Published2007. http://acswebcontent.acs.org/landmarks/landmarks/taxol/tax.html. Accessed November29, 2010.Top HIV Med. 2010;18(5):169-172©2010, International AIDS Society–USADermatologicManifestations ofHIV Infection in AfricaResource CardCards Available NowBased on the Topics in HIV Medicinearticle from February/March 2010,this folding card is available onrequest by visiting www.iasusa.org.Included are brief descriptions ofselected dermatologic manifestations,along with their differential diagnosesand treatment options.172