GENITAL WARTS

A wart is a small growth with a rough texture that can appear anywhere on the body, it looks like a small cauliflower. All warts are caused by Human Papilloma Virus (HPV).

Genital Warts-Standard Treatment Guidelines

Warts occuring on external genitalia are called genital warts. External genital warts are also known as condylomata acuminata. They are one of the most common forms of sexually transmitted diseases. Genital warts are single or multiple soft, painless, flat, papular, or pedunculated growths which appear around the anus, vulvovaginal area, penis, urethra and perineum. May also appear as keratinized papules. Common sites are

• Men: under the foreskin, on the shaft
• Women: around the introitus
• Both: On the anogenital epithelium,within the anogenital tract.

High-risk human papillomaviruses (HPV 16 & 18 serotypes) cause essentially all cervical cancers, most anal and oropharyngeal cancers, and some vaginal, vulvar, and penile cancers. 

There are about 14 high-risk HPV types including HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Two of these, HPV16 and HPV18, are responsible for most HPV-related cancers.

They are caused by a small DNA virus, a papillomavirus belonging to the papovavirus group, which cannot be cultured. Genital warts differ from skin warts histologically and antigenically. Genital warts are nearly always transmitted by sexual contact; autoinoculation from hand to genitals is unusual. The infectivity of sexually acquired warts is about 60%; the incubation period is long, varying from two weeks to eight months.

Genital warts are often asymptomatic and painless. Patients may give a history of suddenly noticing them or noticing them only once their sexual contact has acquired them. Women are more likely to be unaware of warts because it is harder for them to examine their genitalia. Warts flourish in warm, moist conditions, particularly if a discharge or other infections are present.

In men they may be found on the glans and shaft of the penis, prepuce, fraenum and coronal sulcus, urethral meatus, scrotum,
anus, and rectum. Even though anal warts usually occur after anal intercourse they may occur without this. In women the commonest site of infection is the introitus and vulva, but warts may also affect the vagina and (as flat warts) the cervix. Other infected sites may be the perineum, anus, and rectum.

Cutaneous (skin) HPV types

Most HPV types are called cutaneous because they cause warts on the skin, such as on the arms, chest, hands, and feet. These are common warts, not genital warts.

Mucosal (Genital or Anogenital) HPV types

The other HPV types are considered mucosal types because they invade and live in cells on mucosal surfaces. The mucosal HPV types are also called genital (or anogenital) HPV types because they often affect the anal and genital area. These types can also infect the lining of the mouth and throat.   Mucosal HPV types generally don’t grow in the skin or parts of the body other than the mucosal surfaces.

Low-risk mucosal (genital) HPV types:

HPV types that tend to cause warts and rarely cause cancer are called low-risk types. Low-risk genital HPV infection can cause cauliflower-shaped warts on or around the genitals and anus of both men and women. In women, warts may appear in areas that aren’t always noticed, such as the cervix and vagina.

High-risk mucosal (genital) HPV types:

HPV types that can cause cancer are called high-risk types. These types have been linked to certain cancers in both men and women. Doctors worry about the cell changes and pre-cancers these types cause because they are more likely to grow into cancers over time.

Causative organism

• Caused by Human Papilloma virus (HPV) Type 6 or 11 (90% cases).
• HPV types 16, 18, 31, 33, and 35 found occasionally and associated with high-grade intraepithelial neoplasia.
• HPV is a highly contagious virus and is transmitted predominantly through oral, anal, and genital sexual contact
• Sexual contact with an HPV-infected individual results in a 75-percent chance of contracting the virus and developing condylomata acuminata.
• HPV types 6 and 11 rarely give rise to cervical cancers and are thus considered low-risk subtypes. Infection by these genotypes is responsible for 90 percent of the cases of genital wart formation. In contrast, HPV types 16 and 18 are strongly associated with cervical dysplasia and are therefore considered to be high risk, oncogenic subtypes. Evidence for infection by these genotypes is found in up to 70 percent of squamous cell carcinomas (SCC) of the cervix. Human Papilloma Virus (HPV) types 31, 33, 45, 51, 52, 56, 58, and 59 are typically thought to be of intermediate risk since they are often found in association with squamous neoplasms, but have been rarely linked to cervical Squamous cell cancer.
  
• Patients with condylomata Acuminata may be infected simultaneously by multiple HPV strains.
• HPV is a group of nonenveloped, double-stranded deoxyribonucleic acid (DNA) viruses belonging to the family Papovaviridae.
• Viral replication is restricted to the basal cell layer of surface tissues. The virus will penetrate both the cutaneous and mucosal epithelium in search of the appropriate cellular host. It will subsequently invade and infect the basal keratinocytes of the epidermis. The mucosa can be infected anywhere along the genital tract, including the vulva, vagina, cervix, and perianal regions in females as well as the penile shaft, scrotum, periurethral, and perianal regions in males. Infected regions will be marked by a proliferation of viral DNA and the formation of a warty papule or plaque.
• Low-risk HPV subtypes will remain separate from the host cell DNA and thus undergo replication independently. In contrast, high-risk HPV subtypes will incorporate their DNA directly into the host cell’s genetic material. The integration of viral and host cell DNA often results in the dysregulation and uncontrolled activation of the E6 and E7 genes, which promotes the transcription of oncoproteins. These will bind and inactivate tumor suppressor genes p53 and Rb, leading to increased cell proliferation and a greater risk of malignant progression
• Condylomata Acuminata may increase in number and size or, alternatively, undergo a spontaneous regression. Approximately 30 percent of all warts will regress within the first four months of infection. Unfortunately, the majority of genital warts will recur within three months of infection, even after undergoing the appropriate treatments. Significant risk factors for long-term wart persistence include host immunosuppression, infection with high-risk HPV subtypes, and an older patient age. Conversely, the presence of CD4+ lymphocytes in the dermis and the epidermis is generally thought to be associated with elevated rates of spontaneous regression, highlighting the critical role played by the immune system in determining the course of viral infection.

Clinical Presentation (Signs and Symptoms)

• Once infected with HPV, the virus typically requires an incubation period ranging anywhere from 3 weeks to 8 months prior to clinical manifestation.
• Physical symptoms begin approximately 2 to 3 months after initial contact. The virus, however, is also capable of lying dormant within epithelial cells for prolonged periods of time. Infection may thus persist undetected for the duration of an individual’s lifetime with no manifestation of clinically apparent warts
• The manifestation of the Human Papilloma virus (HPV) is development of the viral warts. These warts are usually asymptomatic but depending on the size and anatomic location, can be painful or pruritic.
• Genital warts typically present on the moist tissues of the anogenital area, although they may occasionally develop in the mouth or the throat after oral sexual contact with an infected partner. Condylomata Acuminata have a highly variable appearance and may be flat, dome-shaped, cauliflower-shaped, or pedunculated.
• Genital Warts can persent individually, as a solitary keratotic papule or plaque, but are more frequently found in large clusters. Often genital warts begin as small, nondistinctive 1 to 2mm flesh-colored papules on the skin and may retain this presentation for the duration of the infection. Alternatively, Condylomata Acuminata may grow as large as several inches in diameter, leading to the painful intercourse. The warty contour may also vary in color and appearance, ranging from white to pink, purple, red, or brown and from flat to cerebriform or verrucous.
• Lesions are rarely considered to be painful; however, they are often associated with severe discomfort, burning, and pruritis. Moreover, larger lesions may be subject to bleeding and irritation upon contact with clothing or during sexual intercourse.
  
• Both low-risk (subtypes 6 and 11) and high-risk (subtypes 16 and 18) HPV subtypes have also been associated with the very low-grade, well-differentiated squamous cell carcinoma known as verrucous carcinoma (VC). Verrucous carcinoma is divided into clinico-pathological types based on the anatomic area of involvement: oral florid papillomatosis (oral cavity), giant condyloma of Buschke and Löwenstein (anogenital area), and carcinoma cuniculatum (palmoplantar surface)
• Females are at risk for progression to grade 2/3 cervical intraepithelial neoplasm (CIN) and, if left untreated, can eventually develop invasive cancer of the cervix.
• Penile cancer, which is 10 times less common than cervical cancer, also has a high correlation rate with high-risk HPV infection and history of genital warts.

Warts on the prepuce

warts on the glans penis

Buschke–Löwenstein tumor or Giant condyloma acuminatum  is a rare cutaneous condition characterized by an aggressive, wart-like growth that is a verrucous carcinoma on the penis. The causative organism is Human Papilloma Virus (HPV). Due to their size, these tumors can be locally invasive and destructive, they destroy adjacent structures from compression. In general these masses are benign, but the potential for malignant transformation to squamous cell carcinoma (SCC) exists in the long term, as does the rare risk for metastasis. Buschke-Löwensteoin tumors are frequently associated with HPV subtypes 6 and 11.

Treatment involves surgical resection. Although penile sparing is the goal, total penectomy may be required. They have high recurrence rates.

Uretheral Warts

The human papilloma virus can also infect the urethera and form uretheral warts. They present a special problem for management since they can grow into the urethera or project out of the uretheral meatus (urinary opening). Fulgration of the warts in the urethera has risk of uretheral stricture and require cystoscopic / uretheroscopic fulgration. Long standing HPV infection of the urethera can cause uretheral cancers^{11, 12}.

warts coming out of the uretheral meatus

Differntial diagnosis

• Seborrhoeic keratoses
• Lichen planus and nitidus
• Molluscum contagiosum
• Condyloma lata (syphilis)
• Bowenoid papulosis
• Pearly penile papules
  
• Fordyce’s spots

(Pearly penile papules (PPP) are most common lesions confused with warts. The nodules are lined in symmetrical rows and are located most commonly on the corona of glans penis)

Pearly Penile Papules (PPP) are often confused with warts

PREVENTION AND COUNSELING

General measures as applicable to all patients with suspected Sexually Transmitted Infections

• Blood Test for HIV, Syphilis and Hepatitis B.
• Sexual abstinence during the course of treatment to minimize transmission. (or Avoid unprotected intercourse)
  
• It is important to complete the treatment regimen (Specially for an ulcer/sore). No open ulcers / sore to be present on private parts.
  
• Educate and counsel patient and sex partner(s) regarding (Reproductive tract infections) RTIs/ (Sexually transmitted infections) STIs, genital cancers, safer sex practices.
  
• Both partners must be treated for the suspected organisms / Sexually transmitted diseases like chlamydia, syphilis, urinary tract infections, etc.
• It is best to use barrier contraception like condoms.
  
• Immunization against Hepatitis B and HPV.
• Condoms can offer some protection from HPV infection, but HPV might be on skin that’s not covered by the condom. And condoms must be used every time, from start to finish. The virus can spread during direct skin-to-skin contact before the condom is put on, and male condoms don’t protect the entire genital area, especially for women. The female condom covers more of the vulva in women, but hasn’t been studied as carefully for its ability to protect against HPV. Condoms are very helpful, though, in protecting against other infections that can be spread through sexual activity.

  It’s usually not possible to know who has a mucosal HPV infection, and HPV is so common that even using these measures doesn’t guarantee that a person won’t get infected, but they can help lower the risk.

Key counseling messages to be conveyed to all patients diagnosed with HPV infection

• Correct and consistent male condom use lowers the chances of giving or getting genital HPV, but it does not protect fully. There is always a risk of condom rupture or slipping of condom.
  
• Treatments are available for the conditions caused by HPV but not for the virus itself.
• enital HPV infection is very common and can also be spread by oral, anal and sexual contact.
• It usually has no signs or symptoms until the warts manifest themselves.
• The types of HPV causing genital warts (HPV type 6 &11 ) are different from the ones causing anogenital cancers (HPV types 16 & 18).
• Warts do not affect a woman’s fertility or ability to carry a pregnancy to term, but is large can cause difficulty in Vaginal Delivery.
• To lower the chances of getting infection, limit the number of partners.

HPV vaccines.

Two types which offer protection against the HPV types 16 and 18 that cause 70% of cervical cancers.

• Gardasil: quadrivalent vaccine which also protects against the types 6 and 11. Three doses (0.5 ml IM at 0,2 and 6 months) Most effective when all three doses have been administered before any sexual contact.
• Cervarix: bivalent vaccine against Type 16 and 18 (0.5 ml IM at 0,1 and 6 mths).

Gardasil (HPV9, Merck & Co.).

The recombinant, quadrivalent vaccine was intended for the prophylactic treatment of girls and young women 9 years though 26 years of age for the prevention of the following pathologies caused by HPV types 16 and 18: cervical, vulvar, and vaginal cancer, and condyloma acuminata. In addition, HPV4 is indicated for the prevention of precancerous or dysplastic lesions caused by HPV 6, 11, 16, and 18. Gardasil triggers the formation of host antibodies to the HPV subtypes, which are directly responsible for approximately 90 percent of genital warts and 70 percent of cervical cancers. Gardasil injections are administered in three separate doses and appear to be 99-percent effective in preventing genital wart formation in patients naïve to HPV infection.

Click here for more details about nonavalent HPV (Vaccine Gardasil -9)

Cervarix (HPV2, GlaxoSmithKline)

The vaccine for use in females ages 10 though 25 years. Cervarix is directed against two oncogenic types, HPV 16 and 18, which are associated with cervical cancer, cervical intraepithelial neoplasia grade 1 or worse, and adenocarcinoma in situ. The efficacy of HPV2 has been proven against HPV 16- or 18-related cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ, which was 93 percent (95% CI 79.9–98.3). Comparable to the HPV4 safety data, injection-site pain, redness, and swelling were reported significantly more in the HPV2 group as compared to placebo. Fatigue, headache, and myalgia were the most common general symptoms. The dosing and administration schedules are similar to HPV4 where the second dose is administered 1 to 2 months after the baseline dose, and the third dose is administered six months after the baseline dose.

Overall, the American Cancer Society and Advisory Committee on Immunization Practices recommend routine vaccination of girls age 11 or 12 years with three doses of either HPV2 or HPV4. The vaccination series can be started beginning at the age of nine.

Latest being Gardasil - 9 vaccine which is active against 9 serotypes of HPV virus and there has been change in recommendation for vaccination for women and men.

• COLPOSCOPY / Aceto-white test: Application of 3%–5% acetic acid, which causes HPV-infected genital mucosa to turn white in color on COLPOSCOPY in females.

• LIQUID BASED CYTOLGY (LBC) - for detecting HPV infection in women

• HPV DNA testing (PCR): Not recommended on a routine basis as test results would not alter clinical management of the condition.

• BIOPSY - in suspicious lesions to rule out pre-cancerous lesions
  

Biopsy in Indicated in the lesions in the following conditions

• the disease worsens during therapy
• the warts are pigmented, indurated, fixed, bleeding, or ulcerated.
• the diagnosis is uncertain
• the patient has comprised immunity
• the lesion is atypical
• the lesions do not respond to standard therapy
• The lesion shows a high risk of atypia

Screening for HPV virus

Screening for human papilloma virus is recommended only in women for vagina / cervix. There are currently no recommended screening methods for anal, vulvar, vaginal, penile, or oropharyngeal HPV infections. HPV testing has limited utility in patients at high risk for anal cancer (with high risk behaviour).

Screening in Women

PAP Test

A Pap test is used to find cell changes or abnormal cells in the cervix. Cells are lightly scraped or brushed off the cervix. The slides are stained with Papanicolaou stain and looked at under a microscope to see if the cells are normal or if changes can be seen. The Pap test is a gold standard test for screening of cervix for pre-cancerous cells or early cancer cell (CIN).

The American Cancer Society recommends that women between ages 21 and 29 should have a Pap test every 3 years (at ages 21, 24, and 27) to test for cervical cancer and pre-cancers, while it recommends that women aged 30 to 65 have an HPV test with their Pap test (co-testing) every 5 years to test for cervical cancer.The most common abnormal Pap test result seen is called ASC-US, these ASC-US cells usually are not pre-cancer, but they aren’t quite normal either. If there are ASC-US cells in your Pap test result, an HPV test may be done to see if HPV is causing the cell changes.

The recommendation for gap of 3 years / 5 years is recommended because cell changes in the cervix happen very slowly. It usually takes more than 10 years for cell changes to become cancer. Pap tests have been done every year (annually) in the past, but now it is known that Pap tests are not needed every year – every 3 years is enough.

Human Papilloma test (HPV) TEST in females

HPV is a virus that can cause cervix cell changes. The HPV test checks for the virus, not cell changes. The test can be done at the same time as the Pap test, with the same swab or a second swab. Pap test plus an HPV test (called co-testing) is the preferred way to find early cervical cancers or pre-cancers in women 30 and older.

What does HPV postive test mean

Cervical HPV infection and a normal Pap test result - it means that there is genital human papilloma virus (HPV) presence, but no cell changes were seen in the Pap test. There are 2 options:

Repeat test for HPV and Pap test again in 12 months.

In most cases, re-testing in 12 months shows no sign of the virus, as body immunity would have taken care of the virus. or If the virus does go away and Pap test is normal, then normal screening with PAP test and HPV should be done as recommended every three years from 25  to 49 years of age and every 5 years above 50 years of age.

If the virus is still there or changes are seen on the Pap test, you’ll need more testing. As another option, testing specifically for HPV-16 or both -16 and -18 (the 2 types that are most likely to cause cervical cancer) is done.

If testing shows that you have HPV-16 and/or -18, more testing will be needed  for precancerous cells.

If the test doesn’t show infection with HPV-16 and/or -18, then repeat testing in 12 months with both an HPV test and a Pap test.

Screening in men

Despite the morbidity associated with anogenital condylomas and the mortality associated with anal, penile, and cervical carcinoma as a direct consequence of human papillomavirus (HPV), the routine screening for HPV in immuno competent men is not recommended. However, the high-risk populations of men who have sex with men and men who test positive for human immunodeficiency virus (HIV), in whom HPV infection is pervasive and persistent, may benefit from screening. Therefore, HPV screening, including anal cytology, should be considered for these men in settings where appropriate follow-up, including high-resolution anoscopy, is available. But still there is no recommendation for Human Papilloma virus (HPV) test for men at this time, nor is there any approved HPV test to find the virus anywhere besides the cervix, including the mouth or throat.

The HPV sample collection which yields the most diagnostic sensitivity involves running an emery board across the skin at multiple sites followed by a wet Dacron swab to collect cells. Although 3 HPV DNA testing kits are commercially available for use in women (Hybrid Capture II, Cervista HPV HR and Cervista HPV 16/18), none for use in men. Therefore in men we can use the same kits for screening for HPV.

Finally there is also an argument given that , there’s no useful / advantage to test for a person’s “HPV status,” because an HPV test result can change over a period of months or years as the body fights the virus and body immunity destroys the lesions. 

Penile HPV Screening

Penile screening for HPV is not recommended because of the high prevalence of penile human papilloma virus (HPV) and the generally self-limited duration of infection in immuno-competent men. Little data is available regarding the natural history of HPV infection and the development of PIN (penile cancer in situ) or invasive penile cancer in (men having sex with men) MSM or HIV-positive men.  PIN (penile cancer in situ) cannot be diagnosed by cytology; any suspicious penile lesion requires biopsy for pathology. 

This is how the tests for the HPV sequencing and typing is reported as given in the report below.

This is a report from lab. showing the detection of the HPV virus and the serotyping done showing type 11 serotype.

Click here for The HPV and Men - fact sheet published by CDC (Communicable and Disease control Atlanta America)

Treatment

• No single treatment is ideal for all patients or all warts.
• No definitive evidence that any of the available treatments are superior to any other.
• Spontaneous resolution of lesions may also occur.

Recommended regimens:

NATIONAL AIDS CONTROL ORGANISATION 's (NACO's) :

National Guidelines on prevention, management and control of Reproductive tract infections including sexually transmitted Infections  - Click here to Download PDF file

Treatment of Genital warts - Penile, scrotum, vulval, vaginal  and perineum

• Imiquimod 5% cream or 12.5mg cream (Recommendation -Grade A)  (Imiquimod 5% or 12.5 mg cream is same as 5% imiquimod is 5mg in 100 mg cream base, that means 10 mg in 200 mg cream base or 12.5 mg in 250 mg cream base) - is a patient-applied topical immunomodulatory agent, applied at bedtime 3 times weekly for up to 16 weeks; the treatment area should be washed with soap and water 6-10 hours after the application. Imiquimod cream should be applied 3 times per week (example: Monday, Wednesday, and Friday; or Tuesday, Thursday, and Saturday) prior to normal sleeping hours, and should remain on the skin for 6 to 10 hours. Imiquimod cream treatment should continue until the clearance of visible genital or perianal warts or for a maximum of 16 weeks per episode of warts. If a dose is missed, the patient should apply the cream as soon as he/she remember and then he/she should continue with the regular schedule. However the cream should not be applied more than once a day. Imiquimod cream should be applied in a thin layer and rubbed on the clean wart area until the cream vanishes. Only apply to affected areas and avoid any application on internal surfaces. Imiquimod cream should be applied prior to normal sleeping hours. During the 6 to 10 hour treatment period, showering or bathing should be avoided. After this period it is essential that imiquimod cream is removed with mild soap and water. Application of an excess of cream or prolonged contact with the skin may result in a severe application site reaction. A single-use sachet is sufficient to cover a wart area of 20 cm² (approx. 3 inches²). Sachets should not be re-used once opened. Hands should be washed carefully before and after application of cream. Imiquimod cream therapy is not recommended until the skin has healed after any previous drug or surgical treatment. Application to broken skin could result in increased systemic absorption of imiquimod leading to a greater risk of adverse events. The use of an occlusive dressing is not recommended with imiquimod cream therapy. Imiquimod is a synthetic agent with immune response modifying activity. Imiquimod 5% cream has been used in the treatment of a variety of skin conditions, including basal cell carcinomas and actinic keratoses. Although its precise mechanism of action remains unclear, imiquimod is believed to activate immune cells by binding to the membranous toll-like receptor. This leads to the secretion of multiple cytokines, such as interferon-α, interleukin-6, and tumor necrosis factor-α, which are critical in the induction of an inflammatory response promoting wart clearance. Imiquimod cream should be used with caution in patients with autoimmune conditions. and inflammatory conditoins. In addition, 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. As an immune response modifier (IRM), imiquimod stimulates cytokine production, especially interferon production. Imiquimod does not cure warts, and new warts may appear during treatment. Imiquimod does not fight the viruses that cause warts directly, however, it does help to relieve and control wart production. For the treatment of Condylomata Acuminata, imiquimod is applied at bedtime three times per week for up to 16 weeks. Commonly encountered local inflammatory side effects, such as itching, erythema, burning, irritation, tenderness, ulceration, and pain, have been long-standing issues with the 5% cream. Occasionally, patients may experience systemic side effects of headaches, muscle aches, fatigue, and general malaise. Wart clearance was achieved in 56 percent of patients. with a low recurrence rate (13%). Rarely, intense local inflammatory reactions including skin weeping or erosion can occur after only a few applications of imiquimod cream. Local inflammatory reactions may be accompanied, or even preceded, by flu-like systemic signs and symptoms including malaise, pyrexia, nausea, myalgias and rigors, the application of the cream should be stopped immediately.
  Click here to know more about Imiquad (Imiquimod Cream) 5% cream or (12.5mg in 0.25gm cream sachet)

• Podophyllotoxin 0.05% solution or gel and 0.15% cream (Recommendation - Grade A).

  Podophyllotoxin is a purified extract of the podophyllum plant, it is a non-alkaloid toxin lignan extracted from roots and the rhizomes of podophyllum species. The toxin binds to cellular microtubules, inhibits mitotic division, and induces necrosis of warts that is within 3 to 5 days after administration. The solution is applied with a cotton swab or with a finger to genital warts twice a day for 3 days, followed by 4 days of no therapy; repeated as needed for up to 4 cycles (total wart area treated should not exceed 10 cm², and total volume of medicaton should be limited to 0.5 mL/day). Shallow erosions occur as the lesions necrotize and heal within a few days.

  This treatment option is generally thought to be safe, effective, and can be self-administered. Podophyllotoxin is available as a solution, cream, or gel and must be applied twice daily for three consecutive days of the week, for a maximum of four weeks. Typically, the solution is recommended for penile lesions, whereas cream or gel vehicle preparations are thought to be more comfortable for application to anal or vaginal lesions. various studies have shown successful clearance rates ranging between 45 to 77 percent.  Podophyllotoxin is also associated with rates of recurrence as low as 38 percent. Warts that have not resolved after four courses should be treated by alternative means. 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. Severe systemic effects of peripheral neuropathy, coma, and hypokalaemia can follow application of large quantities. During pregnancy, it is best to offer no treatment. Podophyllin is contraindicated in view of its toxicity and possible mutagenic action, and the warts usually diminish in size once pregnancy has ended. Trichloracetic acid may be used if the lesions are discrete and small and occur on the vaginal wall or vulva.
  

• Sinecatechins 15% ointment (Recommendation - Grade A).

  Sinecatechins is a botanical extract for the treatment of genital warts, making it the first botanical extract to officially receive medical approval. The active ingredient is a green tea extract containing sinecatechins, which is thought to possess antioxidant, antiviral, and antitumor effects. Although the precise mechanism of action remains unclear, sinecatechins is thought to modulate the inflammatory response through the inhibition of transcription factors AP-1 and NF-κB, both of which are induced by reactive oxygen species. They have also been shown to downregulate the expression of cyclooxygenase-2, which has been linked to activation of the prostaglandin E2 system and subsequent epithelial dysplasia.

  Sinecatechins 15% cream is applied topically to warts three times a day for up to four months. Typically, if an improvement is not seen within a few weeks, the treatment is stopped and another option is tried. Several randomized, double-blind, placebo-controlled trials have shown sinecatechins to be significantly more effective than placebo in the treatment of genital warts, with clearance rates as high as 58 percent. Recurrence rates are also relatively low, ranging between 6 to 9 percent at 12 weeks follow up.

  This botanical extract is associated with a number of adverse effects that are thought to occur in approximately 20 percent of users. These events are generally quite mild and typically include redness, burning, itching, and pain at the site of application. More severe reactions associated with this topical product’s use, such as lymphadenitis, vulvovaginitis, balanitis, and ulceration are extremely rare, but have been reported.

• Trichloroacetic acid (TCA) 80–90% solution (Grade B) 

  80 - 90 %, to be every once every two weeks. TCA is a chemically destructive acid that burns, cauterizes, and erodes the skin and mucosa. Generally prepared in 80 to 90% solutions, TCA necessitates administration by the physician. Successful treatment of warts can occasionally occur with as little as a single dose; however, more frequently, several applications are required.

  TCA is an inexpensive, cost-effective treatment that does require prolonged usage and regimen adherence. The destructive nature of the product frequently extends beyond the superficial wart to encompass the underlying viral infection providing for clearance rates that have been estimated at 70 to 80 percent with high recurrence rates of 36 percent.

  Additionally, the low danger of systemic absorption allows for safe application during pregnancy. The main side effects of acid treatments involve pain or burning during administration as well as destruction of the healthy tissue surrounding the wart. The latter can be minimized by washings with soap and sodium bicarbonate immediately following over-application, and dermal injury or scarring is rare. Occasionally, tissue destruction can result in pain, ulceration, and crust formation. High success rates and relatively low morbidity make acetic acid therapy a recommended treatment option for Condylomata Acuminata.Cryotherapy (Recommendation - Grade B).

• Cryotherapy

  Cryotherapy is a process in which the abnormal tissue is frozen through the use of a cooling agent, such as nitrous oxide or liquid nitrogen. Temperatures must be exorbitantly cold so as to cause permanent dermal and vascular damage. This leads to the initiation of an immune repair response, resulting in the necrosis and clearance of the destroyed cells. Generally, this treatment is most effective when used for multiple small warts on the penile shaft or vulva.

  Cryotherapy is considered a fairly inexpensive and highly successful therapy, with a 79- to 88-percent clearance rate seen within the first three treatments. This suggests a more efficacious outcome when compared with Trichoroacetic acid (TCA). Cryotherapy has various limiting factors. Variables in administration, such as the temperature utilized and time of contact, influence efficacy of treatment. Common side effects of cryotherapy include local tissue destruction, such as painful blistering, ulceration, infection, potentially permanent scarring, and loss of pigmentation, which can be slightly more severe than that of TCA therapy.

  Additionally, as with other lesion-directed therapies, cryosurgery does not treat subclinical lesions in the surrounding skin. The recurrence rate associated has been estimated to be between 25 and 40 percent. Other disadvantages of cryotherapy are that multiple outpatient visits are required and the pain associated with its application can limit its repeated use in certain subjects. However, the effects of cryotherapy are entirely local, making it the current therapy of choice for pregnant women with multiple warts.

• Electrosurgery (Recommendation - Grade B). - 

  Electrosurgery involves the use of high frequency electrical currents in the form of thermal coagulation or electrocautery to burn and destroy warty lesions. The desiccated tissue is subsequently removed by curettage. This technique is particularly efficacious when used in the treatment of smaller warts located on the shaft of the penis, the rectum, or the vulva; however, it is not recommended for large lesions as it may lead to permanent scar formation. Electrosurgery is an extremely effective technique, with randomized, controlled trials yielding clearance rates as high as 94 percent measured six weeks post-treatment. These rates, however, tend to normalize after three months, suggesting that electrosurgery is comparable to cryotherapy with regard to its long-term effectiveness. Electrosurgery is also a fairly painful procedure and local or general anesthesia is usually required. Side effects tend to be relatively minimal and are typically limited to post-procedural pain. Electrosurgery followed by imiquad is the treatment of choice for the ano-genital warts¹⁰.
  

Electro-coagulation / Electro-fulgration of warts

Click here to watch this video on youtube

• Surgical excision (Recommendation - Grade B).

  One of the oldest documented treatments for the removal of genital warts, surgical excision was considered for many years to be the primary available option. It involves the physical removal of diseased tissue from the body with scissors or a scalpel, followed by suturing the remaining healthy skin together. It is associated with up to a 72-percent clearance rate, which is evident immediately and often persisting over a year later. This treatment option is suitable for very large lesions that may be causing obstruction and are ineligible or unresponsive to other forms of treatment. Examples include lesions involving the urethral meatus.

  Additionally, surgical excision remains the optimal procedure for the removal of neoplastic lesions suspected of malignant progression, which must be submitted for further histopathological examination. Surgical removal of large lesions is a painful process, which frequently results in bleeding and scar formation. The administration of local or general anesthesia is commonly recommended.

• Laser ablation therapy (Recommendation - Grade B).

  Laser is light amplification by stimulated emission of radiation. Laser is a concentrated energy beam which is focused on the tissue causing it to evaporate. Commonly used laser energy sources are Carbon dioxide laser Argon Laser, Nd-YAG laser, diode laser etc. The intense light energy has the added benefit of providing immediate cauterization of any ligated vessels, ensuring a virtually bloodless procedure. The spatial confinement of the laser beam permits precise tissue ablation resulting in rapid healing with little or no scar formation.

  The efficacy of Laser therapy for Condylomata Acuminata remains debatable. Laser therapy is typically considered to be less effective than other forms of surgical treatment, with clearance rates ranging between 23 to 52 percent. Recurrence rates also tend to be elevated, reaching as high as 77 percent. Side effects are generally mild and limited to the burning of tissue surrounding the lesion. Despite these seemingly unfavorable results, the deep penetrating effect of the laser often allows for a greater and more complete viral attack than seen with other surgical treatment options. This renders it the treatment of choice for immunosuppressed individuals as well as for pregnant women with extensive lesions who remain unresponsive to TCA or cryotherapy.

  Unfortunately, laser therapy is also a rather expensive and complicated treatment option. Furthermore, vaporization of viral lesions can lead to the release of HPV DNA into the surrounding environment. Appropriate measures must therefore be undertaken in order to ensure physicians and assisting personnel are protected from infection. This necessitates the use of specific, virus-resistant masks as well as a vacuum ventilation system in the examination room. Additional risk factors for the transmission of genital warts through vaporization include treatment of malignant HPV subtypes, thinness of skin, and the degree of viral burden.

Genital warts may go away on their own. Also, treating genital warts may not cure a human papillomavirus (HPV) infection. The virus may remain in the body in an inactive state after warts are removed. A person treated for genital warts may still be able to spread the infection. Condoms may help reduce the risk of HPV infection.

Other Misc Therapies

• Intra-lesional Vitamin D injections - Intralesional vitamin D injections

  Vitamin D has been discovered to show a modulatory and regulatory role in multiple processes involving immunity, host defense, inflammation and epithelial repair, in addition to its essential functions in the regulation of calcium homeostasis. Although the exact mechanism of vitamin D activity against warts has not been identified, the effect of vitamin D was speculated to be derived from its immune-regulatory activities, its potential role in regulation of epidermal cell proliferation and differentiation and its modulation of cytokine production. The wart to be injected was cleaned by alcohol and then injected with 0.1 mL of prilocaine (20 mg/mL). 0.2 mL of vitamin D3 (7.5 mg/mL) solution was slowly injected into the base of each wart. The maximum total amount of vitamin D3 injected into a patient in one session was 7.5 mg. The injection was done at 4 weeks interval until clearance or for a maximum of two sessions.

• THUJA - Tincture of Thuja in ointment (local application) / oral drops (systemic administration) in the treatment of warts

  extract from Thuja occidentalis (White cedar tree) - T. occidentalis, an extract from white cedar (Arbor vitae or the white oak) is indigenous to eastern North America and grown in Europe as an ornamental tree. The leaves & twigs on steam distillation yield 0.6 to 1.0% camphor like essential oil called oil of thuja or white cedar leaf oil, sp.gr. 0.925, boiling point 190-206c, easily soluble in alcohol. The main constituent of the oil is d-thujone which is poisonous (W.I., 1976). It acts on the muscles of the uterus, Americans drink a tea of the inner bark to promote menstruation. Thuja also contain volatile oil, sugar, gelatinous matter, wax, resin and thujin. Volatitle oil can be distilled from leaves and used as vermifuge In folk medicine, extract from dried twig tips has been used to treat bronchial catarrh, enuresis, cystitis, psoriasis, uterine carcinomas, amenorrhea, and rheumatism. The drug contains 1.4-4% essential oil (critical factor as medicinal herb), 60% of which is thujone, which corresponds to 2.4% thujone in the whole drug. The pharmacological potential of T. occidentalis has been investigated in various in vitro and in vivo studies. It showed significant increase in interleukin 1, interleukin 6, and tumour necrosis factor alpha and caused local activation of cytokine producing cells for priming without a systemic rise. THUJA causes T-cell induction particularly of Cluster Differentiation 4 (CD 4) positive T-helper cells in connection with an increased production of Interleukin. Thus, thuja has shown definite anti-human immunodeficiency virus-1 activity. A 2-year prospective clinical and therapeutic experience of patients with HPV infection diagnosed based on cytology and or biopsy, which had recurred after treatment found that thuja helped to eradicate the papillomatous lesions. While some studies showed Thuja - 200 systemic theraphy having no effect on warts.

Therapies not generally recommended.

Due to low efficacy and toxicity, routine use of podophyllin, 5-fluorouracil (5-FU), and interferon therapy are not recommended for use in the primary care setting.

• Podophyllin

  was the first topical treatment of genital warts; however, a lack of standardized drug preparation lead to samples that varied greatly in the active ingredient. This increased the likelihood for adverse skin reactions, such as burning, redness, pain, itching, or swelling. In extremely rare circumstances, over-application of podophyllin and excessive systemic absorption has been linked to the development of enteritis, bone-marrow suppression, abdominal pain, and neurological compromise. Podophyllin fails to induce a lasting remission of genital warts and is generally considered less effective than podophyllotoxin, cryotherapy, or electrosurgery when used as individual modalities.

• 5 - Fluorouracil (5-FU) - 

  is one of the oldest chemotherapeutic agents and has been effectively used in the treatment of cancer for more than 40 years. Although not officially approved for use in the treatment of genital warts, topical 5-FU is still seen as a favorable option for urethral warts. The administration of 5-FU has historically been associated with highly variable response rates, and side effects tend to be slightly more severe than those of imiquimod 5% cream with comparable clearance rates yet marginally higher rates of recurrence.

• Interferon therapy -

  has been used predominantly for the treatment of malignant melanoma; however, recent evidence suggests that it may be useful as either an individual or adjuvant to surgical treatment of genital warts. Interferon therapy can be administered systemically, via oral or intramuscular injection, as well as locally, via direct intralesional injections. Typically, 1 to 1.5 million units is used, and injections over three times a week for a duration of three weeks. The use of interferon therapy for the treatment of genital warts remains somewhat controversial. The rate of complete response of systemically used interferon and placebo had no perceivable difference. Due to its direct immune-boosting effects, interferon therapy is likely to promote the clearance of underlying virally infected cells in addition to targeting external lesions. This may ultimately lead to lower rates of recurrence and better long-term results, especially when used synergistically with other treatment modalities. The benefit of interferon therapy as an adjunct treatment remains unclear, with several studies indicating no advantage relative to placebo, while still others show a significant improvement in treatment results. Although this therapy seems promising, further comprehensive research is needed in order to confidently evaluate its effectiveness. Side effects generally include flu-like symptoms, such as headache, nausea, vomiting, fatigue, and myalgia. On rare occasions, systemic interferon therapy has been linked to elevated liver enzymes, bone marrow suppression, bronchospasms, and depression. Intralesional injections are associated with significant pain upon administration, hence the use of local anesthesia is frequently recommended. The use of interferon therapy is an extremely costly procedure and is typically considered the most expensive genital wart treatment. Given the ongoing controversy surrounding the effectiveness of this treatment, interferon therapy is generally considered a last-resort therapy reserved for severe cases that are unresponsive to other forms of treatment.

   

  Generic Name	Brand Name
  interferon alfa-2b	Intron A
  interferon alfa-n3	Alferon N
  interferon beta-1b	Betaseron
  interferon gamma-1b	Actimmune

   

  Interferon can kill viruses and prevent them from reproducing. It also stimulates the body's immune system to fight viruses.
  

  Interferon is given by injection just under the skin at the base of the wart. A common injection schedule is 3 injections a week for 3 weeks or

  2 injections a week for 8 weeks, depending on the type of interferon.
  

   

  Side Effects of Interferons
  

  Interferon injected into warts has side effects such as:

  • Fever and chills.
  • Muscle aches.
  • Pain at the injection site.
  • Utricaria
    
  • A temporary decrease in white blood cells, which fight infection in the body.
  • A decrease in the blood platelets (Thrombocytopenia)
    
  • Flu-Like Syndrome - Flu-like syndrome occurs in a majority of patients because of the "revving-up" of the immune system. It generally occurs within hours of the injection and includes fever, chills, headache, muscle and joint aches, and poor appetite.
  • Fatigue
  • Low White Blood Cell Count (Leukopenia or Neutropenia)
  • Headache
  • Nausea and/or Vomiting
  • Diarrhea
  • Mood Disturbances - Interferon alfa has been reported to cause mood disturbances, depression, anxiety, aggressive behavior, suicidal thoughts, and even suicide.
  • Low Red Blood Cell Count (Anemia)
  • Loss or Thinning of Scalp and Body Hair (Alopecia)

  Less common, but important side effects of Interferons can include:

  • Liver Toxicity
  • Allergic Reaction
  • Thyroid Problems
  • Lung Changes
  • Heart Problems
  • Rash 
  • Vision Changes - While receiving interferon alfa, some patients may develop vision or eye problems like eye pain, swelling, redness or any vision changes, including blurriness, double vision and sensitivity to light.
  • Stroke
    
  • Elevated Cholesterol Level
  • Sexual & Reproductive Concerns - This medication may affect your reproductive system, resulting in the menstrual cycle becoming irregular or stopping permanently. Women may experience menopausal effects including hot flashes and vaginal dryness. In addition, the desire for sex may decrease during treatment

     

   

 Organ Specific Wart Treatments

Cervical warts

• The treatment modality should be changed if a patient has not improved substantially after a complete course
• Cryo cauterization is the treatment of choice.
• Podophyllin is contraindicated.
• Biopsy of warts to rule out malignant change.
• Cervical cytology should be periodically done in the sexual partner(s) of men with genital warts.
• Electro-cautery
• TCA

Vaginal Warts

• Cryo-cuaterisation
• TCA (Tri chloro acetic acid) 80%–90% applied to warts.
• Electro-cautery

Urethral Meatus Warts

• Podophyllin 10%–25% in compound tincture of benzoin.
• Cryotherapy with liquid nitrogen
• Imiquimod use
• Electro-cautery

Anal Warts

• TCA (Tri chloro acetic acid) 80%–90% applied to warts.
• Cryotherapy with liquid nitrogen
• Surgical removal
• Electro-cautery
• Immuno-modulation

Alternative Regimens

• photodynamic therapy
• intralesional interferon
• topical cidofovir.

Special Considerations

Pregnancy

• HPV types 6 and 11 can rarely cause respiratory papillomatosis in infants and children. Whether cesarean
• pelvic outlet is obstructed
• pregnancy is complete.
• genital warts can proliferate and become friable
• Imiquimod, podophyllin not to be used
• Removal of warts during pregnancy can be considered, though resolution might be incomplete or poor until
• Cesarean delivery for women with genital warts is indicated if
• Vaginal delivery would result in excessive bleeding.
• section can prevent this is unclear, hence this is not an absolute indication for caesarean delivery.

HIV Infection

• Lesions are more recalcitrant to treatment
• more likely to develop genital warts
• Same treatment regimes to be followed, however, might not respond as well and might have more frequent recurrences after treatment
• Squamous cell carcinomas arising in or resembling genital warts are more frequent, hence biopsy for confirmation of diagnosis in suspicious cases.
• Screening for anal intraepithelial neoplasia by cytology recommended in HIV-infected MSM (men having sex with men)within the anogenital tract.

 Summarizing in Table format

 Summarizing

References

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