Randomized trials (76,77), including one placebo-controlled trial for acyclovir (78), show effective clinical management of disease with three oral antivirals: acyclovir, famciclovir, and valacyclovir, each of which is an acyclic nucleoside analog. These drugs result in clinical improvement, but do not eradicate latent virus nor do they affect the frequency or severity of recurrences after discontinuation. Topical antivirals offer little benefit and are not recommended.
Effective treatment will decrease shedding, as well as length and severity of symptoms of initial episodes of genital herpes, with both types 1 and 2. According to the Sexually Transmitted Diseases Guidelines, primary infection should be treated with acyclovir, 400 mg tid, acyclovir 200 mg five times daily, famciclovir 250 mg tid, or valacyclovir, 1 g bid (47). Treatment should last for 7 to 10 days. Following the course of medication, treatment is extended if healing is incomplete. Studies comparing these agents have shown equal efficacy.
Antiviral therapy for recurrent genital herpes can be administered either episodically or continously for disease suppression. Effective episodic treatment of recurrent herpes is most effective if initiated within one day of lesion onset, or during the prodrome, if possible (47). Episodic treatment decreases the time to active disease resolution and duration of shedding by one to two days (79). Each of the recommended drugs has been shown in RCTs to be effective (80-82). Recommended regimens include acyclovir (400 mg three times a day for five days or 800 mg bid for five days), famciclovir 125 mg bid for five days), or valacyclovir (500 mg bid for 3 to 5 days or 1 g daily for 5 days) (47). An RCT indicated that a 3-day course of valacyclovir 500 mg twice daily is as effective as a 5-day course (83). Though these drugs are equally efficacious, acyclovir is the least expensive and cost should be considered when choosing agents for prolonged therapy. Clinicians should counsel patients about how to identify recurrences and should provide a supply of antiviral medication for future use.
Herpes simplex virus suppression indicated in patients with more than six outbreaks per year (47). Recommended treatment options include acyclovir (400 mg twice daily), valacyclovir (500-1000 mg once daily), or famciclovir (250 mg twice daily) (47). Valacyclovir 500 mg once a day might be less effective than other dosing regimens in patients with more than 10 episodes per year (47). Daily suppressive therapy decreases symptomatic recurrence by up to 70% to 80%, increases quality of life, and decreases transmission to uninfected partners (79). Therapy with 500 mg of valacyclovir once daily for eight months can reduce disease transmission by up to 48% (79). Nonetheless, clinicians should advise patients that suppressive therapy reduces, but does not eliminate, viral shedding (84). There has been no increase in side effects noted with long-term therapy. Safety has been documented with daily acyclovir therapy for as long as six years and for one year with valacyclovir or famciclovir (79). For many patients, the frequency of recurrences diminishes with time. Because of this fact, periodic discussion regarding discontinuation of suppressive treatment is advised.
It is critical for clinicians to provide education and counseling to infected individuals and their partners. Education should include an explanation of the natural course of the disease, asymptomatic viral shedding, sexual and perinatal transmission, and methods to reduce transmission. Counseling may help, because some patients are troubled more by the psychological manifestations of the disease than the physical symptoms. Initial counseling can be provided at the first visit; the patient may benefit from direction to websites or printed materials for further support.
For HIV-positive patients, lesions may be larger, more painful, with longer healing time and more recurrences. Higher medication dose and longer treatment times may be necessary. Episodic or suppressive antiviral therapy should be considered (47).
Genital Warts (Condyloma acuminata Caused by
Sixty percent of Condyloma acuminata is estimated to resolve spontaneously within two years; nonetheless, patients frequently request treatment (47) for various reasons, including cosmesis and symptom relief. Despite the fact that there is such a high rate of spontaneous resolution, the natural course of the disease varies; the condition may remain unchanged or warts may increase in size or number. Counsel patients that although the lesions may not be present, the virus may always be present in the genital tract, and that recurrences are common, generally in six months after treatment (85). It is unknown whether treatment reduces transmission, as there is no established laboratory marker of infectivity. Existing data indicate that currently available therapies for genital warts may reduce but probably do not eradicate infectivity (86).
There is a variety of treatment options that have been proven in RCTs to be safe and effective. Some treatments have been used for a long time and have shown promising in years of clinical practice. There are other new treatment options the efficacy of which is supported by research data, but that the long-term safety and efficacy have not been demonstrated in practice.
Treatment options may be either physician or patient applied. In the case of patient-applied treatment, if possible, the health-care provider should apply the initial treatment to demonstrate correct application techniques. The two recommended patient-applied treatments are podofilox and imiquimod, the efficacy of which has been supported by data from RCTs.
Podofilox is a purified podophyllin resin available in a 0.5% solution. The medication should be applied to visible warts twice daily for three days, followed by four days without therapy, a cycle that can be repeated as necessary, up to four times (47). There are eight randomized, placebo-controlled trials and many more RCTs supporting the use of podophyllotoxin that report clearance rates of up to 77% within six weeks of treatment (85). Recurrences have been reported for up to 34% of patients followed in clinical trials (87). The safety of podofilox during pregnancy has not been established.
Imiquimod is an immunomodulator with a mechanism of action that is not understood completely, but studies indicate that the chemical induces cytokines, such as IFN-a, thus activating antiviral activity. The 5% cream should be applied at bedtime, three times a week for up to 16 weeks. Six to 10 hours after application, the treatment area should be washed with soap (47). Imiquimod has been studied in a number of clinical trials, including five which were placebo controlled (88,89). Imiquimod is currently FDA-approved treatment for genital warts and has up to 70% clearance rate (85) without recurrence in up to 37% (89). Most studies indicate that this drug is less effective in men than in women (85). Side effects include skin irritation and erythema.
Four recommended provider-administered treatments include cryotherapy, podophyllin resin, acetic acid, or surgical removal. Cryotherapy with liquid nitrogen or cryoprobe can be repeated every 1 to 2 weeks (47). Nonplacebo-controlled clinical trials show efficacy similar to that of bi- and tri-chloroacetic acid, better treatment success than with podophyllin, and possibly less efficacy than electro-surgery (90). The practitioner should attempt to freeze the lesion itself, avoiding the surrounding skin. Complications include burning and ulceration, which usually resolve in 7 to 10 days with little or no scarring. Recurrences rates may be 40% to 75% (85).
This regimen has not been investigated in a placebo-controlled trial; however there are many data comparing podophyllin to the various other treatment options, and there is consensus that efficacy in clearing lesions is similar (86). However, the recurrence rate can be as high as 60%. Provider-administered podophyllin resin is most effective for lesions that are 2 cm or less in diameter (47). A 10% to 25% solution can be applied to visible warts weekly, as necessary. If regression is not achieved after four applications, an alternative therapy should be considered. Transmucosal systemic absorption does occur and this solution should not be applied intravaginally. Complications include a subjective burning sensation or actual ulceration, which can affect as many as 30% of patients (86). Washing the area one to four hours after treatment will minimize severe irritation associated with prolonged exposure. Neurologic, hematologic, febrile complications, and death have been associated with topical podophyllin. Podophyllin is cytotoxic and is contraindicated during pregnancy.
An 80% to 90% solution of bi- or tri-chloroacetic acid is an effective treatment for small lesions, as shown by two RCTs comparing it with cryotherapy (86). Treatment may be repeated weekly, for up to four weeks. Some recommend applying petrolatum ointment, talcum powder, or bicarbonate soda to skin in contact with the treatment area to avoid extensive irritation. The solution can be washed off six to eight hours after treatment and a sitz bath with baking soda may relieve some discomfort. Overall, this regimen has a better side effect profile than podophyllin and can be used safely by pregnant women.
Genital warts can be excised by tangential scissor, shave excision curettage, or punch biopsy, and treatment can be repeated as necessary. RCTs demonstrate no difference in the results achieved by laser and surgical excision, or between the clearance rates as compared with podophyllin. However, surgical excision is more effective in preventing recurrence than is podophyllin (86).
Alternative surgical techniques include loop electrosurgical excision procedures (LEEP) and laser surgery with CO2 laser. Electrosurgery uses thermal coagulation to destroy genital warts. Randomized trials showed a slightly greater efficacy of electrotherapy compared with cryotherapy, but this difference did not persist after three to five months of follow-up. One placebo-controlled trial found electrosurgery to be only slightly more effective in clearing lesions than placebo (86).
Laser therapy uses focused, infrared light energy to vaporize genital warts. In general, laser is reserved for larger lesions and the lesions must be destroyed down to the base to minimize recurrence rates. Some authors suggest that the clearance of warts is better when laser therapy is performed under colposcopic examination. Recurrence rates in a randomized controlled design ranged from 60% to 80% (91).
Several other promising treatment options exist for genital warts. Topical IFN can be used to treat recurrent or resistant genital warts. Treatment efficacy has been supported by three placebo-controlled clinical trials and a trial with podophyllotoxin, which showed wart clearance to be increased substantially. IFN-a and -ft can be used as adjuvants to surgery (92,93). Side effects are generally limited to burning and itching. Systemic IFN has been studied in RCTs with inconsistent results. This drug causes immunosuppression and its risks outweigh the benefits for use as treatment for the treatment of genital warts.
The antiviral cidofovir has been reported effective in limited case series. One study has shown a 65% response rate (85). Typically, this drug is used as a 1% gel applied for five days straight, followed by one week rest, for up to six cycles. Four hours after application, the area must be washed. In a placebo-controlled trial, 47% of cidofovir-treated patient achieved complete remission compared with none of the placebo controls (94). Another placebo-controlled trial in HIVpositive patients showed similar results (95). In HIV-infected patients, one randomized (but not placebo controlled) study showed the efficacy of cidofovir combined with electrosurgery, with a significant reduction of recurrences in patients treated with both cidofovir and electrosurgery in comparison to patients treated by surgery alone (96). These data are based on few subjects and further investigation is necessary; however cidofovir remains a promising option for the future.
Another clinically effective, patient-applied treatment is 5-fluorouracil (5-FU) 5% cream. Small clinical trials support its efficacy as monotherapy (97) and 5-FU with adreneline gel has been tried and proven effective by a randomized, double-blind, placebo-controlled study (98). Associated side effects include erythema, edema, and skin ulceration. Though initial studies produced positive results, with the limited available data and with the potential toxic effects of the drug, this is not currently considered first-line therapy.
Lesions of molloscum contagiusum often involute spontaneously, without scarring. Despite this, the lesions are often treated to prevent patient's discomfort, as well as autoinocculation and transmission.
Mechanical treatments, such as curettage, cryotherapy, and electrosurgery achieve moderate to high initial success rates with variable recurrence rates (99), but can result in pain and mild scarring. Case reports show that CO2 laser therapy may be an effective alternative (100), although keloid formation is possible after treatment (101). Curettage allows for the added benefit of confirmatory diagnosis. However, the success of physical ablation treaments has not been evaluated adequately and placebo-controlled studies are lacking.
Chemical therapies include trichloroacetic acid, 5-FU, bleomycin (99), canthridin, phenol, salicylic acid, lactic acid, and strong saline solution (102). Tretinoin cream may be useful as adjuvant therapy (102). Randomized controlled trials have proven the success of podophyllotoxin as treatment for molluscum contagiosum; however, these results are yet to be reproduced in a study with female participants (103). Local use of cytotoxic agents may result in skin reactions, pain, or adverse systemic effects (99).
Immunomodulators may be of benefit in treating molluscum contagiosum, especially in severe or treatment-resistant cases. In the past, IFN was used to treat molluscum contagiosum; however, results for genital lesions are variable (99). Imiquimod is used currently to treat genital molluscum contagiosum and its efficacy is supported by multiple studies (104,105), which show total clearance rates of 53%, with additional subjects showing substantial reduction in lesion size. Recurrence rates were as low as 7% after 12 months (104). Treatment typically lasts from 4 to 16 weeks. Advantages include ease of application. There are few local side effects, including erythema, pruritis, and erosion; typically, tissue damage is less than damage resulting from ablation.
Currently, cidofovir is being used for treating molluscum contagiosum (106), as are other poxviridae (107). Studies show promising results of treating HIV-infected patients with advanced molluscum contagiosum with topical and intravenous cidofovir (108). Any added benefit in this population may be due to antiviral effects.
Patients should be educated that after treatment, the condition may recur due to re-inoculation from sexual partners.
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