Interferon for the treatment of genital warts: a systematic review

Genital warts, which are also called condylomata acuminata or venereal warts, are the most common sexually transmitted disease (STD) in the general population[1]. The incidence of it is increasing rapidly and closely related human papillomaviruses(HPV) have been associated intimately with cervical neoplasia and other genital tract neoplasms [2‐6]. It is estimated that 1% of sexually active people between the ages of 18 and 45 have genital warts. However, polymerase chain reaction (PCR) testing indicates that as many as 40% of sexually active adults carry HPV that causes genital warts. Genital warts are very contagious and could be spread during oral, genital, or anal sex with an infected partner. About two-thirds of people who have sexual contact with a partner with genital warts will develop warts, usually within three months of contact[7].

Genital warts vary somewhat in appearance. They may be either flat or resemble raspberries or cauliflower. The warts begin as small red or pink growths and grow as large as four inches across, interfering with intercourse and childbirth(in some cases). The warts grow in the moist tissues of the genital areas. In women, they occur on the external genitals and on the walls of the vagina and cervix; in men, they develop in the urethra and on the shaft of the penis.

Current treatment for genital warts is less than satisfying. No clear ideal therapy has been identified. Locally destruction methods, have mainly included surgical excision, electrocautery, cryosurgery and laser vaporization, which may result in scarring and are associated with recurrence. Chemical destructive methods using various acids, such as trichloroacetic or bichloroacetic acid, can be applied by the patients but are often locally irritating and not uniformly effective. Podophyllum resin, Podophyllotoxin, immune inducers (e.g., imiquimod), 5-fluorouracil cream can be used as a topical treatment. However, these medications require several weeks of treatment and may also irritate the skin [8‐11].

In human body, Interferons are a class of small (15-28 kD) protein and glycoprotein cytokines (15-28 kD) produced by T cells, fibroblasts, and other cells in response to viral infection and other biologic and synthetic stimuli. IFNs bind to specific receptors on cell membranes. Their effects include inducing enzymes, suppressing cell proliferation, inhibiting viral proliferation, enhancing the phagocytic activity of macrophages, and augmenting the cytotoxic activity of T lymphocytes. As a curative drug, Interferon could be divided into three major classes (alpha, beta, gamma) on the basis of physicochemical properties, cells of origin, mode of induction, and antibody reactions[12].

Interferon has been shown to be active against HPV both in vitro and in vivo, to protect murine cells against infection with bovine papillomaviruses and to eliminate extrachromosomal viral DNA from infected cells [12, 13]. The chief mechanism of its potential efficacy probably consists of following three fronts: (1) It acts as an antiviral agent; (2) it has an antiproliferative effect; and (3) it elicits an immune response from the host [13‐16]. Based on these properties, interferon may lead to encouraging effects in the treatment of genital warts. It is reported that interferons exert their activities mainly by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies demonstrated that these include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.

By and large, interferon could be used either locally or systemically. Local administrations are mainly composed of intralesional injections and topical applications, in contrast to systemic administrations comprising subcutaneous and intramuscular injections.

Due to the uncertainty of findings from current studies, what is more, HPV-infected patients must be provided with available information with which to make informed decisions regarding what kind of therapy for genital warts is relatively more effective, we aim to determine if there is any evidence from randomized controlled trials (RCTs) that the administration of interferon is efficacious for the treatment of genital warts.

The immune status of the host is fairly crucial in the natural history of wart growth. This could be confirmed by the 20-30% rate of spontaneous remission during the first year of infection among otherwise healthy patients, and, on the other hand by the extensive refractory disease observed among immunosuppressed patients [28, 29]. Conventional treatments for genital warts, including physical or chemical ablation of warts, may cause local issues such as inflammation, pain, ulceration or scars [30]. In addition, these methods only destroy visible lesions, but HPV may persist in normal-appearing epithelium adjacent to treated lesions, which results in a high rate of recurrences[8, 31‐33]. To the contrary, by way of its immunomodulating effect, interferon probably derives from its capacity to eradicate the virus from all the affected cells. For example, a T-helper lymphocyte deficiency, associated to an inversion of T4/T8 ratio has been observed in condylomatous lesions, with improvement of these conditions after interferon therapy[34].

In view of our study, 12 clinical trails were identified which evaluated the efficacy of interferon for the treatment of genital warts. As to complete response rate, they indicated locally-used interferon could achieve a clear beneficial effect while systemically-used interferon could not, both as compared to placebo. With regard to recurrence rate, interferon group appeared to show no lower recurrence rate than placebo group. However, by evaluating the included materials, we discovered that heterogeneity existed between the two groups. Hence, sub-group analysis was carried out under the two circumstances. The results demonstrated that HPV-infected patients with locally administered interferon were less likely than those given placebo to relapse, but that no significant difference in relapse rates was observed between systemic and placebo. As far as safety is concerned, interferon was not toxic and well tolerated, with a relatively low incidence of systemic adverse events, which were mild and did not require treatment interruption. In addition, one trial evaluated the different effects among three intralesional interferon preparations for treating genital warts, indicating that recipients of alpha-n1-, beta-, and alpha-2b-interferons had similar rates of complete resolution of lesions, although the member of patients enrolled in the study did not provide sufficient power to detect small but statistically significant differences among the different interferon preparations. In summary, there are at least two possible explanations for our observation that locally-used interferon could be more effective and achieve better long-lasting effects than systemically-used interferon. Because genital warts is widely regarded as a local illness, it is probable that warts are more sensitive to local administration, optimizing suppression of viral replication and cellular proliferation. Also, systemic administration of interferon may result in much lower intralesional effects of interferon. Thereby, locally-used interferon (intralesional injections or topical applications) are more worthy of recommendation than both systemically-used interferon (subcutaneous or intramuscular injections) and placebo for the treatment of genital warts.

Care should be taken, because both clearance rates and recurrence rates were measured at different times from the start of treatment in the 12 included trials(e.g.,4,8,16 weeks from baseline or different time duration from initial clearance). This may potentially influence the result of this review. However, currently, no standard time scales are available to measure clearance rate and recurrence rate in the treatment of genital warts. So it is difficult for us to make a proper inclusion criteria in study design. We believe that this point has also been considered by the authors of clinical trials. In light of it, we are expecting further research should provide standard time scales to better evaluate the clearance rate and recurrence rate of interferon therapy for genital warts.

Of 12 retrieved studies, only 3 trails describe randomization procedure. Other 9 did not give adequate descriptions of the methodology used. This may have misled us if we had not clarified the details, identifying the trials into category B rather than C. Allocation concealment is an important marker of trial quality. In a study of 250 controlled trials from 33 meta-analyses in pregnancy and childbirth, investigators found that alleged RCTs with inadequate and unclear allocation concealment yielded larger estimates of treatment effects (41% and 33%, respectively, on average)than trials in which authors reported adequate concealment[35]. However, very few potential articles considered for our review reported or performed allocation concealment, leading to high risk of selection bias.

Over and above, none of the studies mentioned blinding to the outcome assessors, which promotes suspicion of detection bias. In addition, 2 of the included studies gave a description of losses of follow up and performed intention-to-treat analyses. 7 studies described withdrawals, dropouts or losses of follow up, but did not perform any intention-to-treat analysis. Other 3 studies did not describe any of them. This may have led to relatively high attrition bias in our study. Otherwise, publication bias may exist as no primary articles reporting negative results were found.

More high quality randomized controlled trials are required for assessing the effects of interferon for the treatment of genital warts. Especially, the randomization procedure should be clearly described, allocation concealment should be emphasized and the approaches should be reported. Besides, we expect that further detailed conducted, placebo-controlled studies of parenterally administered interferons should be carried out to examine the effects of different routes of administration, and more attention should be paid to combined treatment with interferon and other therapeutic agents on rates of regression and recurrence of genital warts.