Unlocking the Immune System

Imiquimod induces immune response to fight viruses that cause genital warts and other skin problems

Genital warts are among the most common but least talked about sexually transmitted diseases (STD's). Medically referred to as condyloma acuminata, genital warts are caused by the human papillomavirus (HPV).

    There is no cure for HPV. Treatments are all directed to the removal of existing, visible warts. Historically, the most common approaches in the management of genital warts have involved surgical removal, cryotherapy, cytodestruction, and the use of chemical cell replication blocker. Until recently, no regimen involved the elimination or reduction of HPV load.

    Used for treatment of external genital and perianal warts, imiquimod (AldaraTM) is the first in a class of drugs called immune response modifiers. A vanishing cream, it represents a new therapeutic approach to genital warts.

    Imiquimod is currently approved only for the treatment of genital and perianal warts. However, recent investigations suggest that imiquimod has beneficial effects for several other dermatologic conditions.

    Some of these studies were presented by Dr. Stephen Peter Shumack, head of the Dermatology Department of St. George Hospital, University of New South Wales, during a recent symposium hosted by 3M Pharmaceuticals. The studies involved the use of Aldara cream in the treatment of other dermatological disorders like common warts, alopecia, molluscum, and keloids for which its use has not yet been approved by the Bureau of Food and Drugs.

    Dr. Georgina Pastorfide, clinical associate professor at the University of the Philippines-Philippine General Hospital and Dr. Marcellano Cruz, head of the HIV Action Team of the East Avenue Medical Center served as panelists while Dr. Francisca Roa, chief of the UP-PGH Multi Disciplinary STD Clinic, served as moderator.

First of a Kind

    Aldara is the first in a new class of drugs called immune response modifiers (IRMs). IRMs demonstrate both anti-viral and anti-tumor activity. In the treatment of genital and perianal warts, IRMs act by stimulating the patient's own immune system to fight the virus and eliminate the warts.

    "Topical application of Aldara cream induces a local immune response. As such, cytokines are released in response to the topical application of imiquimod cream," explained Dr. Shumack. Cytokines then activate Langerhans cells--the primary antigen presenting cells in the epidermis--to process the human papillomavirus (HPV) antigen, after which they travel to lymph nodes and activate HPV-specific T-cells to enter the bloodstream. HPV-specific T-cells, in turn, travel to the wart to kill HPV-infected cells, which are then phagocytized by monocytes and macrophages.

    Already proven is imiquimod's ability to induce a local immune response. In the preclinical studies, a range of cytokines is released in response to the topical application of imiquimod. In particular, these are alpha interferon and interleukin.

Why Treat Genital Warts?

    "About one percent of sexually-active adults develop genital warts. And if we look hard enough, in 75 percent of people, we will find HPV exposure. Aside from genital warts, the more important thing to note is the oncogenic potential of various HPV subtypes. Oncogenesis is predominantly associated with subtypes 16 and 18, and has been strongly associated with cervical cancer.

    Treating genital warts with Aldara, said Dr. Shumack,

    provides relief of symptoms, and offers good cosmesis. Treatment (of genital warts) can help improve self-esteem of patients as they do not like having genital warts. Imiquimod cream does not work overnight. It can take at least eight weeks to start seeing a response, although most of the activity usually occurs in 12 weeks.

    Occasionally though, treatment for genital warts can show efficacy earlier, and sometimes may take up to 16 weeks, but the most notable advantage over other treatment is the low recurrence rate of 13 percent.

    "Aldara is approved for the treatment of external genital warts," said Dr. Shumack. However, current practice reflects that 80 percent of the prescriptions written for Aldara are for non-approved indications.

Molluscum Contagiosum

    One of the more well-documented non-approved indications for imiquimod is the treatment of molluscum contagiosum. "In an open study of 15 patients treated with imiquimod five percent cream for one week, lesions cleared in eight patients and four patients had a greater than 50 percent reduction in size and number of molluscum contagiosum. Treatment time was about nine weeks, and most patients had manifested improvement by the fourth week.

    Sharing her experience with Aldara, Dr. Georgina Pastorfide, recommends a once-a-day bedtime regimen of Aldara cream which is to be left on the lesion site overnight.

    Expounding on the topical use of Aldara for keloid and molluscum contagiosum, Dr. Marcellano Cruz, former president of the Philippine Leprosy Society and Philippine Society of Venereologists and fellow of the Philippine Society of Cutaneous Medicine, said improvement in the size of the lesion is usually seen after a month or two of imiquimod application.

Common Warts

    Aldara cream has also been shown to be beneficial in the treatment of common warts. A study involving 50 patients with extensive common warts showed that common warts were eliminated in 15 patients. Thirteen other patients had manifested greater than 50 percent reduction in the size and number of warts. Mean treatment time was about nine weeks. More importantly, no recurrence was noted in patients treated with Aldara cream.

    The problem in the treatment of common and plantar warts with Aldara is the penetration of the drug into the keratinized skin. To deal with this, the area may be occluded and liquid nitrogen may be used prior to application of Aldara.

    Dr. Francisca Roa, vice president of the Philippine Dermatological Society and section chief of the Multi-disciplinary STD Clinic of the University of the Philippines-Philippine General Hospital, advises patients to soak the affected area for 10 to 30 minutes and to debulk a little portion of the lesion before applying imiquimod. With this protocol, absorption of the drug is facilitated, explained Dr. Roa, which leads to better treatment response. For genital warts, she recommends using liquid nitrogen or CHD laser for debulking.

    Dr. Roa, however, cautions against the use of steroid concomitant with imiquimod, as the two drugs have contradictory effects on immune regulation.

    Periungal warts are likewise treated with Aldara after the immersion of the affected digit in tap water for ten minutes. In treating periungal warts, however, Dr. Pastorfide recommends putting the affected area under occlusion for the whole night. Decrease in the size of the wart is achieved after around two months, and there is said to be little recurrence.

Basal Cell Carcinoma

    In basal cell carcinoma, Dr. Shumack explained that the cure rate is about 90 percent for superficial BCC, and 73 percent for nodular BCC. The difference, he explained is related to penetration because "nodular BCCs usually have intact epidermal barrier."

    Dr. Shumack presented four phase II dose response studies in the US and Australia involving some 400 patients. The Australian study yielded 88 percent cure rate over six weeks of therapy. The US study had 87 percent cure rate at six to 12 weeks of treatment.

    One big advantage of Aldara, he noted, is that "it leaves no histological evidence" of BCC. "There is almost no scarring, which is why it has become more commonly used in the US and Australia," he added.

Other Uses

    Other off-label indications considered for Aldara include management and treatment of mycosis fungoides, lentigo maligna, keloids, actinic porokeratosis, alopecia areata, and Bowen's disease.

    Dr. Shumack reported that in at least one study, all 12 keloid patients treated with Aldara responded with no recurrence, way above the normal 50 percent recurrence rate one would expect with any other form of treatment. Likewise he cited anecdotal reports of successful treatment of alopecia areata with Aldara. A report of ten patients treated three times a week titrated to daily said the treatment was not only successful; some of the patients started growing hair again.

    Dr. Pastorfide also cited her own experience in treating alopecia areata with Aldara cream.

    Dr. Shumack said Aldara is safe to use, as there is very little systemic absorption associated with its topical application. More importantly, there is no effect on the systemic CD4 levels.