A 32-year-old African American woman with human immunodeficiency virus 1 (HIV-1) and a 3-year history of extensive facial molluscum contagiosum (MCV) presented to the dermatology clinic for treatment. The patient had been treated with multiple therapies, including liquid nitrogen, topical 0.05% liquid tretinoin, and 0.5% topical podofilox, with no improvement and some secondary irritation to the latter 2 therapies.
At her initial appointment, she was taking nelfinavir mesylate (Viracept), 750 mg 3 times daily; stavudine (Zerit), 40 mg twice daily; didanosine (Videx), 200 mg twice daily; trimethoprim-sulfamethoxazole (Bactrim DS), 800 mg/160 mg every day; and fluconazole (Diflucan), 100 mg every day. She had been receiving nelfinavir, stavudine, and didanosine for 5 months and trimethoprim-sulfamethoxazole and fluconazole since shortly after her diagnosis 3 years earlier. Her CD4 T-cell count was 0.004×109/L (38/mm3) and the viral load (Roche Amplicor HIV-1 RNA–polymerase chain reaction [RNA-PCR]) was at 2900 RNA copies/mL. This represented an approximately 1.5 log reduction in her initial viral load and had remained relatively stable during the past few months.
On examination, there were papules and large nodules and plaques predominantly on the face. They ranged in size from 3 to 20 mm, with areas of depressed scarring and postinflammatory hyperpigmentation (Figure 1).
Our goal was to find a therapy for this severely immunosuppressed patient with disfiguring MCV lesions. Although she had shown a marked decrease in her viral load with multidrug antiviral therapy, her CD4 T-cell count remained low, and she showed no improvement in her MCV lesions.
The patient was started on imiquimod (Aldara), 5% cream, 25-mg single-use packets. She applied 2.5 packages of the imiquimod cream 3 times per week at bedtime. She left the medication on her face for 6 to 10 hours, washing it off later with mild soap and water. At the 1-month follow-up, most of the lesions showed mild erythema and some superficial erosions with stable but continued postinflammatory hyperpigmentation. All of the lesions had flattened and were reduced in diameter by approximately 25% to 50%. For the second month, she used 2 packages of imiquimod to the residual lesions as previously described. By the end of the second month, the lesions nearly were resolved clinically with stable postinflammatory hyperpigmentation. For the third and last month of therapy, the patient used only 1 packet of the imiquimod to the residual lesions. By the end of the third month, the lesions appeared cleared with minimal erythema, some residual depressed scarring, and residual postinflammatory hyperpigmentation. The patient was given 4% hydroquinone cream to be applied daily for the hyperpigmentation. The hyperpigmentation showed progressive improvement during the next few months. Following her last month of therapy, her CD4 T-cell count was 0.007×109/L (70/mm3) and the viral load was at 4000 RNA copies /mL.
The patient was seen 5 months after therapy, with no evidence of recurrent lesions (Figure 2). Her CD4 T-cell count was 0.006×109/L (60/mm3) and the viral load was at 3600 RNA copies/mL.
Molluscum contagiosum virus is a large double-stranded DNA virus that is either considered a member of the Orthopoxvirus genus of the family Poxviridae or an unclassified poxvirus. It has a worldwide distribution, and, with the eradication of smallpox (variola virus), MCV is the most common pox viral pathogen for humans.1-7
Lesions of MCV occur in skin, with only rare reports of mucous membrane involvement.1-3 The MCV infections occur in young children, sexually active adults, and in some immunosuppressed patient populations. Although widespread lesions do occur in patients with HIV-1, head and neck lesions are most common, followed by genital involvement.1-4,8,9 In addition to the typical umbilicated papules, patients with HIV-1 may also present with verrucous, warty papules of MCV that may become giant lesions greater than l cm in diameter.1-4,8,9 In patients without severe immune suppression, lesions produced by MCV typically regress spontaneously, usually within months.1-7 However, with persistent immunosuppression associated with HIV-1 infection, MCV lesions may be persistent and deforming.1-7 After beginning multidrug antiviral therapy, including protease inhibitors, some patients with HIV-1 and chronic MCV lesions have shown clearing of their lesions.10 The dramatic decrease in viral loads seen in some patients following these regimens, with or without increases in peripheral CD4+ T-cell counts, may potentate the patient's immune response to MCV. However, although this patient did have a marked decrease in her viral load with multidrug therapy, she had had no clearing of her MCV during a 5-month period.
The MCV genomes encode a conserved domain of epidermal growth factor–like (EGF) proteins. It is these EGF proteins that vary between MCV subtypes.11,12 Patients with HIV-1 have a disproportionate percentage of MCV due to subtypes other than type 1, which is by far the most prevalent subtype. The variability in EGF proteins in different subtypes, in combination with host-specific factors related to HIV-1 infection and perhaps other concurrent infections, may be a factor in explaining the large verrucous lesions that are seen in some HIV-1–positive patients.1,2,6 A cytokine–helper T-cell 2 (TH2) pattern of immune deregulation is seen with progression of HIV-1–positive disease.13,14 This pattern of immune deregulation may play a role in decreased resistance to infections in patients with HIV-1, but especially in the decreased ability of these patients to fight intracellular infections.8
In the United States, imiquimod, 5% cream (Aldara), is available for treatment of external genital and perianal warts. Imiquimod has no direct antiviral effects; however, it can induce a number of proinflammatory cytokines that may potentiate immune responses.15-17 Human epidermal keratinocytes can produce increased levels of interleukin 6 (IL-6), IL-8, interferon alpha (IFN-α), and tumor necrosis factor α (TNF-α) after stimulation with imiquimod.15,16 Although fibroblasts appear to show a less pronounced response to imiquimod, with less elevation of IL-8 and TNF-α, Langerhans cells and macrophages are major contributors to the increased cytokines seen locally with topical imiquimod through their production of INF-α and TNF-α.16
The INF-α may potentate cellular responses against viruses through a number of different mechanisms. Not only does INF-α have a direct anti-inflammatory effect, INF-α also increases the frequency of INF-γ producing CD4+ T cells and can induce a TH1 cytosine profile in some T-cell clones, promoting IgG2a synthesis and inhibiting IgE.18-21 The INF-α also induces the expression of major histocompatibility complex (MHC) class I cell surface antigens that are necessary for cytotoxic CD8+ T-cell responses. It antagonizes the suppressive effects of IL-4 on INF-γ production and inhibits antigen-induced proliferation and cytokine production by TH2 clones.18-21 Through the induction of INF-γ , INF-α also potentates natural killer cell cytotoxicity, macrophage activation, and MHC class II expresssion.20 The TNF-α may potentate the clearing of MCV lesions locally through its direct cytotoxic effects and by the production of free radicals.22-24 The IL-8 and IL-6 are both proinflammatory, and together with the other cytokines they can potentially moderate the down-regulation of immune and inflammatory responses induced by MCV products.
Because MCV does not appear to be capable of developing latency, clearing of lesions is more consistently a reflection of long-term cure than with other viruses, such as herpes simplex virus and human papilloma virus, and even in this severely immunosuppressed patient treatment with imiquimod appears to have resulted in cure.
Because imiquimod potentates the immunologic and inflammatory responses against MCV, it has the potential to be used not only as a single agent, but also in combination with topical antivirals, such as topical cidofovir, which are active against MCV.25
Accepted for publication April 30, 1999.
The opinions or assertions herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of the Navy, or the Department of Defense.
Corresponding author: COL Kathleen Smith, MC, USA, Department of Dermatology and Pathology, National Naval Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889-5600.
2.Epstein
WL Molluscum contagiosum.
Semin Dermatol. 1992;11184- 189
Google Scholar 3.Lewis
EJLarn
MCrutchfield
CE An update on molluscum contagiosum.
Cutis. 1997;6029- 34
Google Scholar 4.Schwartz
JJMyskowski
PL Molluscum contagiosum in patients with human immunodeficiency virus infection.
J Am Acad Dermatol. 1992;27583- 588
Google ScholarCrossref 5.Senkevich
TGBugert
JJSisler
JRKoonin
EVDarai
GMoss
B Genome sequence of a human tumorigenic poxvirus: prediction of specific host response evasion genes.
Science. 1996;273813- 816
Google ScholarCrossref 6.Yamashita
HUemura
TKawashima
M Molecular epidemiologic analysis of Japanese patients with molluscum contagiosum.
Int J Dermatol. 1996;3599- 105
Google ScholarCrossref 7.Mark
RBuller
LBurnett
JChen
WKreider
J Replication of molluscum contagiosum.
Urology. 1995;213655- 659
Google Scholar 8.Kunkel
SLStrieter
RMLindley
IJWestwick
J Chemokines: new ligands, receptors and activities.
Immunol Today. 1995;16559- 561
Google ScholarCrossref 9.Smith
KJSkelton
HGYeager
J
et al. for the Military Medical Consortium for the Advancement of Retroviral Research (MMCARR), Cutaneous findings in HIV-1-positive patients: a 42-month prospective study.
J Am Acad Dermatol. 1994;31747- 754
Google Scholar 10.Costner
MCockerell
CJ The changing spectrum of cutaneous manifestations of HIV disease.
Arch Dermatol. 1998;1341290- 1292
Google ScholarCrossref 11.Porter
CDBlake
NWArchard
LC Structure and activity of epidermal-growth-factor-like peptides: induction of basal cell proliferation by a poxvirus gene product?
Bio Soc Trans. 1988;16671- 674
Google Scholar 12.Porter
CDArchard
LC Characterization and physical mapping of molluscum contagiosum virus DNA and location of a sequence capable of encoding a conserved domain of epidermal growth factor.
J Gen Virol. 1987;68673- 682
Google ScholarCrossref 13.Clerici
MShearer
GM A T
H1-T
H2 hypthesis of HIV infection new insights.
Immunol Today. 1994;15575- 581
Google ScholarCrossref 14.Romagnani
SDel Prete
GRavina
MA
et al. Role of T
H1/T
H2 cytokines in HIV infection.
Immunol Rev. 1994;14073- 92
Google ScholarCrossref 15.Kono
MDKondo
SShivji
GM
et al. Effects of the immunomodulator R-837 on cytokine gene expression in the human epidermal carcinoma cell line COLO-16.
Lymphokine Cytokine Res. 1994;1371- 76
Google Scholar 16.Fujiswa
HSivji
GMKondo
S
et al. Effect of a novel topical immunomodulator, S-28463, on keratinocyte cytokine gene expression and production.
J Interferon Cytokine Res. 1996;16555- 559
Google ScholarCrossref 17.Imbertson
LMBeaurline
JMCouture
AM
et al. Cytokine induction in hairless mouse and rat skin after topical application of the immune response modifiers imiquimod and S-28463.
J Invest Dermatol. 1998;110734- 739
Google ScholarCrossref 19.Parronchi
PDe Carli
MManetti
R
et al. IL-4 and INF (alpha and gamma) exert opposite regulatory effects on the development off cytolytic potential by the T
H1 and T
H2 human T-cell clones.
J Immunol. 1992;1492977- 2983
Google Scholar 20.Finkelman
FDSvetic
AGresser
I
et al. Regulation by interferon alpha of immunoglobulin isotype selection and lymphokine production in mice.
J Exp Med. 1991;1741179- 1188
Google ScholarCrossref 22.Stewart II
WE The Interferon System. New York, NY Springer-Velag NY Inc1981;
23.Obrador
ENavarro
JMompo
I
et al. Regulation of tumour cell sensitivity to TNF-induced oxidative stress and cytotxicity: role of glutathione.
Biofacts. 1998;823- 26
Google ScholarCrossref 24.Schulze-Osthoff
KFerrari
DLos
MWesselborg
SPeter
ME Apoptosis signaling by death receptors.
Eur J Biochem. 1998;254439- 459
Google ScholarCrossref 25.Meadows
KTyring
SParvia
A
et al. Resolution of recalcitrant, molluscum contagiosum virus lesions in human immunodeficiency virus–infected patients treated with cidofovir.
Arch Dermatol. 1997;133987- 990
Google ScholarCrossref