a Departments of Infectious Diseases and c Genito-urinary Medicine, Royal Hallamshire Hospital, Sheffield; b Division of Genomic Medicine, F Floor, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
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Abstract |
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Introduction |
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Imiquimod (Aldara, R-837, S-26308) and resiquimod (R-848, S-28463) are members of a new group of low molecular weight compounds, the imidazoquinolinamines3 (Figure). These have been shown to have properties as immune response modifiers in vitro and in vivo, and demonstrate antiviral and anti-tumour activity via endogenous cytokine production.3,4 In vitro studies using non-human or human monocytes treated with imiquimod or resiquimod have reported increased mRNA in cell lysates and/or cytokine levels in supernatants of IFN-
, interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-
.3,57 In comparison with lipopolysaccharide or viral stimulation, IFN-
fold induction was greater than that of other cytokines.3,57 IL-1
, IL-1 receptor antagonist, IL-6, IL-8, IL-10, granulocyte-macrophage colony stimulating factor, granulocyte colony stimulating factor and macrophage inflammatory protein-1
were also upregulated.3 Resiquimod is more potent at inducing cytokine expression than imiquimod. The clinical significance of many of these cytokines is uncertain due to the variable experimental conditions employed. In vivo studies of humans and animals treated with topical 5% imiquimod cream or topical 0.11.0% resiquimod gel have, however, confirmed the induction of mRNA for IFN-
and TNF-
in treated but not untreated skin.8,9 In addition to monocytes, keratinocytes in skin were stimulated to produce cytokines. Imiquimod upregulated IL-6 and IL-8 in vitro,3 while resiquimod induced mRNA for IL-1
, IL-8, TNF-
and transiently IFN-
.10
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Langerhans' cells (LC), which are potent antigenpresenting cells in multiple locations including the skin, demonstrated functional activation and enhanced induction of T-lymphocyte proliferation in response to imiquimod or resiquimod treatment.14 LC migration to draining lymph nodes was also enhanced, which could facilitate antigen presentation to T-lymphocytes.15 A Th-1 cytokine profile, including IFN-, was preferentially induced in mitogen-stimulated T-lymphocytes exposed to imiquimod or resiquimod.16 This was mediated by upregulation of IFN-
and IL-12 in monocytes and macrophages, an effect seen to a greater extent with resiquimod than with imiquimod treatment.16 B-lymphocytes proliferated, became activated and were stimulated to produce immunoglobulin.17 In these studies resiquimod was more potent at inducing lymphocyte proliferation and was also capable of aiding immunoglobulin class switching, unlike imiquimod.17 These links between innate and acquired immune responses suggest the potential usefulness of imiquimod, and in particular, resiquimod, as agents that could enhance vaccine responses.
Imidazoquinolinamines demonstrate indirect antiviral activity in vivo owing to cytokine induction, which inhibits viral replication directly and stimulates innate and acquired antiviral immune responses. In patients treated with 5% imiquimod cream, human papillomavirus (HPV) DNA and mRNA for the L1 gene were significantly decreased in association with a clinical response to therapy.8 Animal models, case reports and open-label studies have variously demonstrated the antiviral effect of imiquimod against HSV, Rift Valley fever virus, Banzi virus and in the treatment of molluscum contagiosum.3,18,19 In most circumstances the observed antiviral effect has been associated with topical administration. The pharmacokinetics of topical administration are incompletely delineated but systemic absorption has not been detected, so the effect is local.3 The cream is usually applied to clean dry skin and left for 610 h before being washed off.
Resiquimod has greater potency at inducing cytokine expression than imiquimod but whether this will increase its antiviral spectrum is presently unknown. It may, however, be more useful than imiquimod in treating HSV-2 and may also be used in HCV infection.20,21 In a guinea-pig model of HSV-2 infection, resiquimod was effective when administered by dermal, subcutaneous or intravaginal routes before infection.20 Antiviral activity is related to induction of serum 2',5'-oligoadenylate synthetase activity. Resiquimod was also found to decrease recurrence of HSV-2 when administered subcutaneously in this model. Unlike imiquimod, for which pre-systemic biotransformation has limited its oral bioavailability, resiquimod may be administered by the oral route and trials are under way to assess its use in anti-HCV therapy, for which IFN- forms the cornerstone of therapy.21
Imiquimod 5% cream (Aldara) is licensed for the treatment of anogenital warts in immunocompetent patients. The evidence supporting this license comes from three prospective, double-blind, randomized, vehicle-controlled trials.2224 In these trials 698 immunocompetent individuals were randomized to receive topical therapy with imiquimod 5% cream, 1% cream (22,23 only) or vehicle control. The topical treatment was applied daily22 or three times a week23,24 for 16 weeks or until lesions cleared. Complete clearance of warts was observed in 3752% of those treated with 5% cream, 1421% of those treated with 1% cream and 011% of those treated with vehicle control by intent-to-treat analyses.2224 For complete responders, relapse rates at 1012 weeks were 1319% for 5% cream, 017% for 1% cream and 010% for vehicle control. Response rates were higher in female as compared with male patients. Local skin effects, including erythema, excoriation, flaking and erosion, were common but usually well tolerated. Ulceration was also noted in a minority of patients. These side-effects were associated with itching, pain and burning but systemic side-effects were not reported as occurring with greater frequency in the treatment group.22 None of these studies analysed changes in HPV DNA. Subsequent clinical audit has demonstrated a similar response rate.25
Therapy of anogenital warts in HIV-seropositive individuals has been less effective. In a randomized, double-blind, vehicle-controlled trial of imiquimod 5% cream administered three times a week in 100 HIV-seropositive individuals receiving antiretroviral therapy and with CD4 T-lymphocyte counts >100 x 106 cells/L, complete response rates were seen in only 11% of the imiquimod group, compared with 6% of the control group, after 16 weeks of therapy, a result that was not statistically significant.26 A 50% reduction in wart size was, however, demonstrated in 38% of those who received imiquimod as compared with 14% of controls (P = 0.01), and the therapy was well tolerated. The number of individuals in this study whose HIV RNA plasma copy number was undetectable was not stated. Further studies are needed to address how this response rate can be improved.
In a further, double-blind, randomized, vehicle-controlled trial, 100 immunocompetent patients with molluscum contagiosum were randomized to receive a control or 1% imiquimod cream three times daily, 5 days a week for 4 weeks.27 Clearance of lesions was demonstrated in 82% of the imiquimod-treated individuals but only 16% of controls. Relapse rates after 10 months of follow-up were very low.
Resiquimod may also find a role in the treatment of HPV or molluscum contagiosum infection. In addition, it may be particularly useful against HSV-2, either as an agent to prevent recurrence or as a vaccine adjuvant in the presence of HSV glycoproteins. In a randomized study involving 52 immunocompetent individuals with a history of six or more recurrences of herpes genitalis per year, resiquimod demonstrated clinical efficacy.28 Resiquimod gel at various concentrations, or vehicle control, was administered to lesions within 24 h of onset and treatment continued for 3 weeks. The median time to first recurrence was 169 days for the combined resiquimod treatment group as compared with 57 days for the control group (P < 0.01). In the 6 months of follow-up 32% of the resiquimod but only 6% of the control group had no recurrences (P < 0.05). A European multicentre Phase III randomized double-blind study is currently determining the efficacy of 0.01% resiquimod gel at preventing recurrences of anogenital herpes.
It is likely that immune response modifiers similar to imiquimod and resiquimod will find other clinical indications but many questions remain to be answered. Imidazoquinolinamines may have efficacy in the treatment of conditions for which IFN- is currently employed, such as Kaposi's sarcoma (KS) and chronic HCV infection. Cutaneous lesions such as HSV genital ulcers or KS lesions could be treated using the topical preparations already studied. However, conditions such as chronic HCV hepatitis would require an oral formulation and resiquimod may be better suited to these uses.21 Interestingly, Phase I trials of an oral formulation of imiquimod have already been conducted in HIV-seropositive individuals and patients with cancer.29 The potential role of oral imiquimod in the therapy of HIV infection is intriguing but caution is warranted; in this trial of oral imiquimod in HIV-seropositive individuals two of 10 (20%) individuals demonstrated dramatic increases in plasma HIV RNA copy number, while two individuals demonstrated significant decreases. Transcription factors critical for imiquimod-mediated cytokine induction, such as NF
B, also upregulate HIV replication, and the significance of LC migration to lymph nodes in HIV immunopathogenesis needs to be investigated. Imiquimod, and to a greater extent resiquimod, have also demonstrated leishmanicidal activity due to nitric oxide synthesis in macrophages in an animal model of cutaneous leishmaniasis, suggesting other potential uses of imidazoquinolinamines against infection.30
In addition to the therapy of established infection the imidazoquinolines may have activity in therapy of cancers such as basal cell carcinoma (BCC). Of 24 patients treated, at various dosing intervals, with topical 5% imiquimod cream, 20 (83%) lacked evidence of BCC on biopsy 6 weeks after therapy compared with only one of 11 (9%) of the group treated with vehicle control.31 It remains to be established whether oral formulations of imidazoquinolines will extend the range of potential cancers that could be treated.
Furthermore, the role of imidazoquinolines as vaccine adjuvants requires investigation. Adjuvants are essential to enhance the efficacy of vaccination with weak immunogens. The development of safe and effective adjuvants to boost cell-mediated immunity is a priority of human vaccine research. Imidazoquinolines induce Th-1-mediated immune responses as opposed to the Th-2 responses associated with the use of alum, which is currently used as an adjuvant in human vaccines.32 This is the result of IFN- and IL-12 production, which enhances IFN-
production. The potential advantages of inducing Th-1 responses in response to immunization could have far-reaching consequences in the management of infections and cancer.
Many more studies are urgently needed to determine the safety and applicability of these novel immunomodulating agents in the therapy of HIV infection, other infectious diseases, cancer and in the development of immunization protocols. However, they are already demonstrating clinical utility in the therapy of genital warts, molluscum contagiosum and, potentially, herpes genitalis.
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Notes |
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References |
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