Genital warts are a symptom of certain types of human papillomavirus (HPV) infection and result in significantly reduced quality of life. A number of treatment options are available, but efficacy rates vary dramatically between treatments.
External genital warts (EGWs) are one of the most commonly reported sexually transmitted diseases worldwide (Maw 2004). EGWs, also known as condylomata acuminata, are epidermal growths caused by the human papillomavirus (HPV), on the anogenital areas of both females and males (Narsinghani et al 2016). The specific cause of the occurrence of these warts is HPV-induced infection and replication in the lower levels of stratified epithelium, which manifests clinically as warty growths and dysplastic areas of cellular proliferation (Wiley et al 2002).
About 50% to 60% of sexually active women aged 18 to 49 years have been exposed to HPV infection, but only 10% to 15% will have genital warts (Narsinghani et al 2016). Although benign, EGWs can cause significant physical discomfort, including inflammation, fissuring, itching, bleeding and dyspareunia, although they are benign growths (Maw 2004). Additionally, they are perceived as cosmetically unacceptable, and can cause psychological distress, anxiety, guilt, anger, loss of self-esteem and relationship problems for patients (Maw 2004). They also create concerns about future fertility and of cancer risk (Lacey et al 2012).
There is no certain way to tell who will develop health problems from HPV and who will not (CANSA 2017). In most cases HPV goes away by itself before it causes any health issues, and most people who become infected with HPV do not even know that they have it (CANSA 2017). Most patients only complain of the presence of the lesions, which are otherwise symptomless, although symptoms can include itching, bleeding, fissuring or dyspareunia (Lacey et al 2012).
EGWs can develop months or even years after contracting HPV (CDC 2015). HPV types that cause genital warts can be passed on to another person even in the absence of visible signs of warts (CDC 2015). Sex partners also tend to share HPV, even though signs of HPV such as warts might occur in only one partner or in neither partner (CDC 2015). A vaccine that prevents genital warts (Gardasil) is available for both males and females, but it will not treat existing HPV or genital warts (CDC 2015). This vaccine can prevent most cases of genital warts in persons who have not yet been exposed to wart-causing types of HPV (CDC 2015).
Risk factors for HPV infection
HPV infections are common and risk factors for HPV infection include (CANSA 2017):
- Number of sexual partners – the greater your number of sexual partners, the more likely you are to contract a genital HPV infection. Having sex with a partner who has had multiple sex partners also increases your risk.
- Age – common warts occur most often in children and adolescents. While plantar warts may occur in adults, they’re more likely to initially surface during childhood. Genital warts occur most often in adolescents and young adults.
- Weakened immune systems – people who have weakened immune systems are at greater risk of HPV infections. Immune systems can be weakened by HIV/AIDS or by immune system-suppressing drugs used after organ transplants.
- Damaged skin – areas of skin that have been punctured or opened are more prone to develop common warts. For example, people who bite their fingernails are more likely to develop warts around their fingernails.
- Personal contact – touching someone’s warts or not wearing protection before contacting surfaces that have been exposed to HPV – such as public showers or swimming pools – may increase one’s risk of HPV infection.
To date, more than 120 distinct subtypes of HPV have been identified, with approximately 40 different subtypes capable of infecting the anogenital tract (Yanofsky et al 2012). HPV types 6 and 11, which rarely give rise to cervical cancers and are thus considered low-risk subtypes, are responsible for over 90 percent of the cases of genital wart formation (Yanofsky et al 2012). The HPV types most commonly found in cancerous tissue are types 16, 18 and 33 (O’Mahony 2005). Other subtypes that can cause EGWs are types 30, 40 to 45, 51 and 54 (CANSA 2017). Genital warts are therefore mostly a cosmetic nuisance, since they are caused by low-risk HPV types, have no oncogenic potential and are not linked to cervical cancer (O’Mahony 2005).
Physicians should not immediately assume that skin irregularities associated with HPV types 6 and 11 indicate EGWs, though. For example, a rare variant of HPV 6⁄11 infection is the giant condyloma or Buschke-Lowenstein tumour, a form of verrucous carcinoma, characterised by aggressive local infiltration into underlying dermal structures (Lacey et al 2012). Management requires specialist surgical and oncological referral, with recent reports suggesting good outcomes with chemo-radiotherapy (Lacey et al 2012).
Diagnosis of anogenital warts is usually made by visual inspection, but can be confirmed by biopsy, which is indicated if lesions are atypical (e.g. pigmented, indurated, affixed to underlying tissue, bleeding or ulcerated lesions) (CDC 2015). Biopsy might also be indicated in the following circumstances, particularly if the patient is immunocompromised (including those infected with HIV) (CDC 2015):
- the diagnosis is uncertain
- the lesions do not respond to standard therapy; or
- the disease worsens during therapy.
Lesions are often found in sites that are traumatised during intercourse and may be solitary, but frequently there will be 5 to 15 lesions of 1-5 mm diameter (Lacey et al 2012). Warts may also coalesce into larger plaques, but this is more commonly seen with immunosuppression and in diabetes (Lacey et al 2012). Furthermore, anogenital warts may vary significantly in colour, from pink to salmon red, and from white to greyish white to various shades of brown (Lacey et al 2012). Although warts tend to be non-pigmented, pigmented lesions are mostly seen on the labia majora, penile shaft, pubis, groin, perineum and perianal area (Lacey et al 2012).
Because genital warts can be sexually transmitted, patients with genital warts benefit from testing for other STDs and sexual activity should be avoided with new partners until the warts are gone or removed (CDC 2015). HPV might remain present and can still be transmitted to partners even after the warts are gone (CDC 2015).
Because warts might spontaneously resolve within one year, an acceptable alternative for some persons is to forego treatment and wait for spontaneous resolution (MMWR 2015). That being said, the current treatment options are largely centered upon removal of the warty growths rather than elimination of the underlying viral infection (Yanofsky et al 2012). Since EGW treatments do not remove the viral infection, it is common for genital warts to recur after treatment, especially in the first 3 months (CDC 2015). Because of this, it is necessary for successful treatments to stimulate the immune system to recognise the virus (O’Mahony 2005).
Treatments for genital warts can be classed as either provider- or patient-applied (Maw 2004). Traditionally, genital warts have been treated with provider-applied therapies, often requiring multiple clinic visits for successful wart clearance (Maw 2005). Commonly used physical treatment methods include cryotherapy, trichloroacetic acid, laser, and electrocautery, but many patients respond extremely well to home therapies with either podophyllotoxin or imiquimod (O’Mahony 2005).
This is consistent with the shift in focus over recent years towards topical, patient-applied treatments (Maw 2004). Patients prefer the comfort and dignity of home treatment, and this should be the first-line of treatment for the majority of patients (O’Mahony 2005). Clinician feedback over the years has indicated that patient preference is of major importance and the majority of patients want a treatment they can apply in the comfort of their own homes, as opposed to regular clinic visits (O’Mahony 2005). The most common patient-applied treatments are imiquimod, podophyllotoxin and 5-fluorouracil and of these, only imiquimod and podophyllotoxin are recommended in both Europe and the US (Maw 2004).
It is unclear whether treatment of visible genital warts has any effect on transmission of infection, and most currently available treatments do not attempt to treat the underlying problem of viral infection; they only cosmetically remove warts (Maw 2004). Therefore, in contrast to other sexually transmitted diseases, the primary treatment goals associated with EGWs resulting from HPV are to ameliorate symptoms, remove symptomatic warts and minimise psychological sequelae where possible (Maw 2004).
Podophyllotoxin is a purified extract of the podophyllum plant, which binds to cellular microtubules, inhibits mitotic division, and induces necrosis of warts that is maximal 3 to 5 days after administration (Yanofsky et al 2012). Podophyllotoxin preparations are cheap and relatively fast acting, making them first-line treatment options for fleshy warts (O’Mahony 2005). Warts that have not resolved after four courses should be treated by alternative means (Yanofsky et al 2012). Adverse effects tend to be fairly common, especially with the first course of therapy and include pain, inflammation, erosion, burning, or itching at the application site, often as a result of excessive treatment administration on the part of the patient (Yanofsky et al 2012). Although it can cause destruction of warty tissue, it can also damage normal skin (O’Mahony 2005).
Cryotherapy, a provider-applied therapy, removes warts by freezing resulting in cytolysis which destroys the wart and a small area of surrounding healthy tissue (Maw 2004). Liquid nitrogen can be applied either by means of a spray device or directly with a swab for about 20 seconds (Maw 2004). Health-care providers must be trained on the proper use of this therapy because over- and under-treatment can result in complications or low efficacy (CDC 2015). In addition, pain during and after application of the liquid nitrogen, followed by necrosis and sometimes blistering, is common (CDC 2015). Cryosurgery does not treat subclinical lesions in the surrounding skin, and the resulting recurrence rate associated with this provider-applied methodology has been estimated to be between 25 and 40 percent (Yanofsky et al 2012).
Imiquimod is a novel synthetic molecule with potent immune-modifying activities, often formulated in a 5% vanishing cream as Aldara (Slade et al 1998). The molecule does not demonstrate direct antiviral activity, but through induction of cytokines results in immune-based resolution of wart tissue and reduction of viral burden (Slade et al 1998). Phase III trials of imiquimod have demonstrated that patients who experience complete clearance of either new or recalcitrant warts tend to remain clear, possibly related to Th1 immune recognition and memory (Slade et al 1998). Self-application, good tolerability and a unique mechanism of action combine to make imiquimod a reasonable first-line therapy for genital warts (Slade et al 1998).
Imiquimod-treated patients have been shown to have a decrease in viral load measured by HPV DNA, a decrease in messenger ribonucleic acid (mRNA) expression for markers of keratinocyte proliferation, and an increase in mRNA expression for markers of tumor suppression (Yanofsky et al 2012). In a patient survey, patients rated imiquimod 5% cream as better than other EGW therapies in terms of (O’Mahony et al 2001):
- Overall satisfaction
- Time to clearance
- Covenience; and
- Lack of associated pain.
The same study found that over 50% of patients rated imiquimod better than cryotherapy, podophyllotoxin and laser therapy (O’Mahony 2001). Recurrence rates are also consistently lower after treatment with imiquimod than they are after podophyllotoxin treatment, even though their efficacy rates for clearing EGWs are similar (Yanofsky et al 2012). Imiquimod has been shown to be effective in many studies, including three randomised, placebo-controlled, double-blind trials in which clearance rates were 37–52% after 8–16 weeks of treatment (Maw 2004). When considering a broader selection of trials, clearance rates for imiquimod were 33–72% for up to 16 weeks of treatment (Maw 2004).
During the three-month follow-up phase of an imiquimod clinical trial, baseline warts that completely cleared during therapy recurred in 13% of patients who were treated with 5% imiquimod (Edward 2000). Additionally, imiquimod is suitable for all types of external genital warts (keratinised and non-keratinised), thus making it an ideal choice for first-line therapy (Maw 2004).
Studies have indicated that application site reactions were the most common adverse event associated with imiquimod use and were generally mild to moderate (Garland et al 2006). The most frequently reported side-effects include pain, itch, erythema, burning, irritation, tenderness, ulceration and erosion at the application site, but these local reactions are likely related to the beneficial inflammatory response induced by imiquimod (Maw 2004).
For the treatment of EGWs, imiquimod 5% is applied at bedtime three times per week for up to 16 weeks (Yanofsky et al 2012). Imiquimod 3.75% cream should be applied once at bedtime, but must be applied every night (CDC 2015). With either formulation, the treatment area should be washed with soap and water 6 to 10 hours after the application (CDC 2015).