Obstetrics and Gynecology

Viral Vulvovaginal Disease

Genital Herpes: Herpes Simplex Virus (HSV-1 and HSV-2)

1. What every clinician should know

Herpes simplex virus (HSV)

Herpes Simplex type 1 (HSV-1) and Herpes Simplex type 2 (HSV-2) are ubiquitous, host adapted pathogens which cause infections worldwide. HSV-1 and HSV-2 are also referred to as genital herpes. Genital herpes is one of the most common infective causes of genital ulceration in developed countries, and at least 50 million people are infected in the United States. Infection is life-long, and once established, there is no treatment to eliminate it. Genital herpes is frequently under-recognized because infection is often subclinical and asymptomatic in 80% of cases. However, in immunocompromised hosts, infections can cause life-threatening complications.

Pathogenesis

HSV-1 and HSV-2 are double stranded DNA viruses. Exposure to HSV at mucosal surfaces or abraded skin sites permits viral entry and replication in cells of the epidermis and dermis. HSV enters sensory or autonomic neuronal cells and is transported to nerve cell bodies in ganglia, where it can become latent. During latency, HSV is maintained in a repressed state compatible with the cell's survival and normal activities. Reactivation occurs when normal HSV gene expression resumes, with appearance of the virus on mucosal surfaces. Studies have demonstrated HSV viremia in 30-40% of persons with primary HSV-2 infection.

Transmission

Transmission can take place via contact with persons with active ulcerative lesions, which is the most efficient means. It can also take place via persons without clinical manifestation of disease who are shedding HSV or on whose mucosal surfaces the virus is replicating. Common source of exposure to HSV infection is usually from sexual or close contact. Transmission of HSV-2 may be more efficient from men to women. This may partly be due to the higher rate of disease recurrences in men which may make them more infectious. Asymptomatic shedding occurs in both men and women, but is more easily detected in women, mainly from the cervix and vulva.

Transmission of infection from mother to baby usually occurs during vaginal delivery (85% of transmissions) and is dependent on the prevalence of genital viral shedding at the time of delivery. Intrauterine (5%) and postnatal transmissions (10%) are rarer. Intrapartum transmission is rare in recurrent maternal infections (3-5%), but rises to between 33% and 50% where the mother has a first episode genital infection, with the greatest neonatal morbidity following late gestation primary infections.

Incidence and prevalence

Genital herpes is usually caused by HSV-2, although 10-30% of cases involve HSV-1. In recent times, there has been a trend of HSV-1 causing genital herpes in young adults. Approximately one out of six people between the ages of 14-49 years in the U.S. have genital HSV-2 infection. The prevalence of HSV infection worldwide has increased over the years, making it a major public health concern. Early diagnosis and prompt and appropriate therapy are important in the management of the disease.

HSV-1 and HSV-2

HSV-1 is usually acquired in childhood by contact with oral secretions that contain the virus. More than 90% of adults have antibodies to HSV-1 by their fifth decade of life.HSV-2 antibody prevalence rates correlate with sexual activity and vary greatly among population groups, including by sex, age, socioeconomic status, and race. HSV-2 antibody prevalence rates average about 5% higher among women than among men. HSV-1 infection is acquired at an earlier age than HSV-2 infection.

HSV-2 genital infection in children can be an indication of sexual abuse. Increased age after onset of sexual activity and total number of sexual partners are independent factors associated with increased seroprevalence of HSV-2 antibodies. In populations of low- socioeconomic status, most persons acquire HSV-1 infection before the third decade of life. In a national health survey conducted in the United States, seroprevalence of HSV-2 antibodies was 45% in blacks, 22% in Mexican Americans, and 17% in whites.

HSV-2 infection is associated with a two to four fold increase in HIV-1. HSV-2 is more frequently reactivated in and transmitted by people who are co-infected with HIV-1 than in those who are not. Moreover, most areas of the world with a high HIV-1 prevalence also have a high HSV-2 prevalence.

Clinical features

Primary infections are usually accompanied by systemic signs, longer duration of symptoms, and higher rate of complications. Conversely, recurrent episodes are milder and shorter in duration. In general, after a prodromal period (typically less than six hours in recurrent HSV-1) of tingling discomfort or itching, clusters of small tense vesicles appear on an erythematous base. Clusters vary in size from 0.5-1.5 cm, but may coalesce. Vesicles typically persist for a few days, then rupture and dry, forming a thin, yellowish crust. Healing generally occurs 8-12 days after onset.

Lesions may occur on the labia, clitoris, perineum, vagina, and cervix. They may occur around the anus and in the rectum of woman who engage in receptive rectal/anal intercourse. Genital HSV infection may cause urinary hesitancy, dysuria, urinary retention, or constipation. Scarring may follow healing in many cases, and skin lesions can also develop secondary bacterial infection.

Primary genital herpes

Primary genital herpes can be caused by both HSV-1 and HSV-2 and can be asymptomatic. The clinical features and course of primary genital herpes caused by HSV-1 and HSV-2 are indistinguishable, but recurrences are more common with HSV-2. Systemic symptoms include fever, headache, malaise, and myalgia, while local symptoms include herpetic vesicles on the external genitalia, labia majora, labia minora, vaginal vestibule, and introitus. It also causes itching, vaginal and urethral discharge, and tender inguinal adenopathy.

In moist areas, the vesicles rupture, leaving exquisitely tender ulcers and vesicles can continue to erupt over one to two weeks. The ulcerative lesions persist for 4-15 days until crusting and reepitheliazation occurs. In cases of vaginal infection, the vaginal mucosa is inflamed and edematous. The cervix is also involved in 70%-90% of cases and is characterized by ulcerative or necrotic cervical mucosa. Cervicitis can be the sole manifestation in some patients. Dysuria can be severe causing urinary retention and HSV can be isolated in the urine. HSV-1 infection causes urethritis more often than HSV-2 infection. Conversely, 15% of cases are associated with non-lesional clinical syndromes. The median duration of viral shedding is about 12 days.

Subclinical genital herpes

Primary genital herpes is usually asymptomatic with 70-80% of seropositive women having no history of genital herpes. Of note, asymptomatic viral shedding may occur in 1-2% of infected immunocompetent persons and maybe as high as 6% in the first few months after acquisition of the infection. This is a very important property of the virus to remember in the prevention of sexual and perinatal transmission of infection.

Risk factors for primary infection include unsafe sexual practices, immunosuppression, atopic eczema (at risk for eczema herpeticum), and trauma to exposed skin. Risk factors for reactivation include immmunosuppression, HIV/AIDS, organ transplant and chemotherapy. In patients with HIV/AIDS infection, herpetic infections can be particularly severe. Progressive and persistent esophagitis, colitis, perianal ulcers, pneumonia, encephalitis, and meningitis may occur.

Condyloma acuminata/ANO-genital warts/Human Papilloma Virus infection

This is the most common viral sexually transmitted disease in the United States, with women accounting for 67% of infections.

Pathogenesis

Ano-genital warts are caused by Human Papilloma Viruses (HPVs) which are small, nonenveloped, double stranded DNA viruses. In a condyloma, viral replication is associated with excessive proliferation of all of the epidermal layers except the basal layer.

An effective immune system is important in the resolution of HPV infection. HPV infection occurs more frequently and is more severe in patients with primary and secondary immunodeficiencies. Severe and frequent HPV disease is seen in HIV/AIDS patients. The prevalence of this condition is higher in patients with lower CD4 T cell counts and higher HIV-1 RNA viral levels. In addition, compared with HIV- seronegative subjects, AIDS patients have an increased risk for malignant transformation.

Epidemiology

Genital HPV infections are classified according to their risk of causing cervical cancer. Low risk HPV types 6 and 11 cause 90% of anogenital warts. These warts affect approximately 1% of the population and an annual incidence of 6 million has been estimated in the United States. This makes anogenital warts the most commonly acquired viral sexually transmitted disease in the United States. It is estimated that at least three quarters of the population may have been infected in their lifetime. Prevalence of condyloma is higher in patients who are HIV positive or who have other forms of STD.

Transmission and incubation

Evidence that anogenital warts are sexually transmitted includes the observation that the age of onset is similar to that of other STDs and that genital warts develops in about two-thirds of sexual contacts of patients with anogenital warts. In addition, patients with anogenital warts often have other concomitant STDs or a history of STD's. Vaginal-penile intercourse is the most common route of transmission. However, HPV can be transmitted among "virgins" via non penetrative sexual skin to skin contacts.

Genital warts develop between three to four months but the range could vary from three weeks to eight months, and infection is usually transient and cleared within two years. Persistent infections in the setting of other clinical risk factors (HIV) are associated with the development of squamous cell carcinoma.

Serotypes

There are over 70 distinct HPV subtypes and approximately 35 are specific for anogenital epithelium. The low risk subtypes such as HPV 6 and11 do not integrate into the host genome and are most frequently associated with benign condyloma and low grade intraepithelial neoplasia.

Risk factors

Disease is sexually transmitted in women and is primarily caused by vaginal/penile intercourse. Other methods of transmission include anal/penile, digital/anal, oral/anal and digital/vaginal. Risk factors include having a higher number of life time sexual partners, having a higher number of sexual partners in the past year, being single, lower socioeconomic status, low educational level, non- Hispanic black race and immunosuppression, e.g., HIV. HPV infections are more common in immunosuppressed individuals.

Clinical features

In women, the vulva is the most common area affected. The vagina, anus, cervix and urethra can also be affected. About three quarters of patients with anogenital warts are asymptomatic. However, women may complain of pruritus, bleeding, burning, tenderness, vaginal discharge or pain. They may also complain of a growth or swelling in the perineum/perianal area.

Anogenital warts are flesh to gray colored, hyperkeratotic, exophytic papules, either sessile on the skin or, more frequently, attached by a short, broad peduncle. Lesions could be smooth, pearly papules to more jagged, acuminate growths. They vary in size from less than a millimeter in diameter to several square centimeters when they merge into plaques. Condyloma can occasionally form large exophytic masses that can interfere with intercourse, vaginal delivery, or defecation. Large lesions are commonly seen among HIV positive women.

2. Diagnosis and differential diagnosis

Diagnosis of HSV general infection

Diagnosis is often clinical and based on characteristic lesions. Clinical diagnosis should be confirmed with laboratory testing, especially in patients with severe infection, if the patient is immunocompromised or pregnant, or lesions are atypical in appearance.

Clinical presentation

History and examination has a low sensitivity for detecting genital herpes infection ranging from 19% to 39% of women in published studies. Although many patients show the classical, vesicular, ulcerative lesions of genital herpes disease, atypical presentations are increasingly being recognized and laboratory testing should be done to confirm clinical diagnosis.

Laboratory detection

Diagnosis is best confirmed by isolation of the virus in tissue culture. Cell culture and polymerase chain reaction (PCR)-based testing of the lesion are the preferred tests for a patient presenting with active lesion. PCR-based testing has the greatest overall sensitivity and specificity, while viral culture has a sensitivity of approximately 50% and depends on how the sample was collected.

Viral tissue culture

This is the most common diagnostic test used in clinical practice but the diagnostic yield of culture is highest in the early stages of disease, when lesions are typically vesicular, and declines rapidly as the lesions begin to heal. Fluids and material for culture should be obtained from the base of a vesicle or of a freshly ulcerated lesion or unroofed lesion. Failure to properly collect and transport the sample could lead to false negative results. This modality can yield positive results within 48 hrs of inoculation. Immunofluorescent staining of the tissue culture cells can be used to quickly identify HSV and can distinguish between types 1 and 2.

HSV PCR

This is the most sensitive test but may not be available in all clinical settings. Real -time HSV PCR assays have emerged as a more sensitive method to confirm HSV infection in clinical setting where available. It is particularly useful for the detection of asymptomatic viral shedding.

Tzanck smear

The characteristic cytologic changes induced by HSV can also be demonstrated in Tzanck smears (a superficial scraping from the base of freshly ruptured vesicle stained with Wright's-Giemsa stain). A positive Tzanck result is the finding of multinucleate giant cells, but it does not differentiate between HSV-1 and HSV-2. Rapid diagnosis is possible based on the histologic appearance of the lesion. Multinucleated giant cells and epithelial cells containing eosinophilic intranuclear inclusion bodies distinguish the lesions of herpes viruses. This is a less sensitive test.

Other tests

Monoclonal antibodies directed to type-specific antigens in enzyme immunoassay (EIA) and fluorescence -immunoassay formats are the methods most laboratories use in HSV diagnosis. Cells scrapped from ulcer bases can also be stained with a direct fluorescent antibody (DFA) which differentiates HSV-1 from HSV-2. DFA can also distinguish different herpes viruses and nonherpes viruses.

Serological assays

Highly sensitive and specific type-specific serological assays include immunodot enzyme assays (IEA). Type specific IgG testing directed against glycoprotein G of HSV-1 or that of HSV-2 can distinguish HSV-1 infection from HSV-2 infection. When measured against western blot, sensitivity of 97-100% and specificity of 94-98% has been documented. Serologic testing is recommended to confirm a clinical diagnosis of genital herpes in patients with recurrent genital symptoms, atypical lesions, or with healing lesions and negative HSV cultures. Type specific HSV antibodies can take from two weeks to three months to develop. Thus, in a person with newly acquired herpes, the initial absence of IgG antibodies specific for glycoprotein G and subsequent development of such antibodies after 12 weeks confirm new HSV infection.

Summary

A positive HSV tissue culture or HSV DNA test indicates an active HSV-1 or HSV-2 infection. A negative test result indicates HSV virus was not isolated but it does not definitely rule out the presence of the HSV virus. It could be a false negative result based on improper collection or improper transportation of sample to laboratory. The presence of HSV-1 or HSV-2 IgG antibodies indicates a previous infection. Negative HSV antibody results implies that exposure to HSV is unlikely or more importantly could imply that patient has primary HSV and has not seroconverted. Some patients can take up to 12 weeks to seroconvert.

Differential diagnosis of HSV general infection

HSV should be distinguished from herpes zoster, vulvo-vaginal candidiasis, syphilis, chancroid, lymphogranuloma venerum, donovanosis, and hand-foot- and -mouth-disease.

Diagnosis of HPV genital infection

Diagnosis is usually visual. During physical examination, the extent of involvement should be documented by examination, speculum exam, colposcopy, or an oscopy as required. If needed for better appreciation of lesion, application of 3-5% acetic acid can be performed. Acetic acid to the lesion turns the lesion white in appearance, which facilitates better identification. Typically, lesions are shiny white patches with poorly defined borders that may have an irregular surface containing characteristic capillary loops.

Clinicians should consider a biopsy for patients who do not respond to therapy after the provider administered treatment or do not resolve after six months of treatment, for those patients who are immunosuppressed, for those with very large pigmented lesions, especially if ulcerated, and in patients with atypical presentation who are over the age of 40 years.

Differential diagnosis of HPV genital infection

This condition should be distinguished from:

  • Condyloma lata (secondary syphilis)

  • Squamous cell cancer of the anogenital area can exist concurrently with condyloma acuminata

  • Molluscum contagiosum

  • Micropapillomatosis labialis

  • Seborrheic keratoses

  • Herpes simplex virus

  • Bowenoid papulosis

  • Malignant melanoma

  • Angiofibroma

  • Hymenal remnant and vulvar intraepithelial lesion

3. Management

Management of HSV

Medical management is centered on the use of specific antiviral agents and the goal of therapy is to reduce morbidity and to prevent complications. Although the same medications are active against HSV-1 and HSV-2, the location of the lesions and the chronicity (primary or reactivation) of the infection determines the dosage and duration of antiviral agent.

Life-threatening HSV infections in immunocompromised patients require high dose intravenous acyclovir, often started empirically. Appropriate wound care is needed, and treatment for secondary bacterial skin infections may be required. In some cases, consultation with a dermatologist may be needed, and in immunocompromised patients, consultation with a HIV specialist may be required.

Saline bathing and use of appropriate analgesia are recommended. Lidocaine has been safely used as a topical anesthetic in the management of genital herpes. Also, counsel patient about transmission risks, including subclinical shedding and the limited impact of condoms and antivirals.

Antiviral chemotherapy

Indications include primary infection, recurrent infection, and suppression of outbreaks.

Acylovir

Synthetic purine nucleoside analogue with activity against a number of herpes viruses (HSV and varicella zoster). It is highly selective for virus-infected cells because of its high affinity for viral thymidine kinase enzyme. It is the most frequently used agent for HSV infections and is significantly cheaper than Valacyclovir and Famciclovir, with equal efficacy. Acyclovir is available in intravenous, oral and topical formulation. Side effects include transient renal insufficiency due to crystallization of compound in renal parenchyma and this adverse effect can be reduced by making sure the patient is well hydrated and also by slow administration of the drug.

Valacyclovir

This is a prodrug that is rapidly converted to the active drug acyclovir. It is more expensive than acyclovir but has a greater bioavailability, and less frequency of dosing when compared to acyclovir. It is the only agent shown to reduce transmission of HSV-2 infection between partners. Oral dose of 4 g per day or greater has been associated with thrombotic thrombocytopenic purpura after extended use in HIV-positive persons.

Famciclovir

This prodrug inhibits viral DNA synthesis and replication when transformed into its active metabolite, penciclovir. It has excellent bioavailabilty and used against herpes simplex and varicella-zoster viruses.

Ganciclovir

This agent is active against HSV-1 and HSV-2, but unfortunately more toxic than acyclovir, valacyclovir, or famciclovir.

First episode genital herpes

Treatment duration is 7-14 days. Treatment includes:

  • Oral acyclovir: 200 mg five times a day or 400 mg three times a day

  • Oral valacyclovir: 1 g twice a day

  • Oral famciclovir: 250 mg three times a day

Symptomatic recurrent genital herpes

Treatment shortens lesion duration. In one study, patients who self-initiated therapy at the prodromal phase had more benefits from episodic treatment compared with those who started treatment within 48 hours of lesion appearance. Early initiation of therapy (within 24 hours of symptoms) leads to faster resolution of recurrent cutaneous lesions and clinical symptoms. Short-course (one to three day) regimens are preferred because of low cost and convenience. Treatments include:

  • Oral acyclovir: 800 mg three times a day for two days or 400 mg three times a day for five days or 200 mg five times a day for five days

  • Oral valacyclovir: 500 mg twice a day for three or five days

  • Oral famciclovir: 750 mg or 1000 mg twice a day for one day, or a 1500 mg single dose, or 500 mg stat followed by 250 mg every 12 hours for three days, or 125 mg twice a day for five days

To suppress recurrent genital herpes, treatment must be effective against symptomatic reactivation and asymptomatic shedding. Treatment includes:

  • Oral acyclovir: 400 mg twice a day or 800 mg daily

  • Oral famciclovir: 250 mg twice a day

  • Oral valcyclovir:

    • <10 episodes per year: 500 mg PO daily

    • >/= 10 episodes per year: 1 g PO daily or 500 mg PO twice a day

Acyclovir-resistant infections

Resistant strains are usually from immunocompromised patients. These strains are infrequent, but clinical suspicion of resistance should arise if HSV persists despite adequate acyclovir doses and blood levels. Intravenous forscanet (40 mg/kg, over 1 hour, every 8 or 12 hours) should be given until the lesion heals. The optimal duration of therapy and the usefulness of its continuation to suppress lesions are unclear. Medication may cause renal toxicity and electrolyte imbalances. Daily cutaneous application of trifluorothymidine or 1% cidofovir gel may also be beneficial.

Management of HPV

The goal of treatment is to alleviate symptoms and reduce viral burden with the hope of preventing progression of disease. Treatment may also improve psychological distress and cosmesis. Wart removal does not eradicate /cure HPV infection. In general, no single therapy is superior, but some therapies are contraindicated in pregnant women.

Health-care providers need to assess their patients and decide if self-administered therapy is preferred over office administered therapy. They should be comfortable with at least one provider-applied and one patient-applied therapy. In addition, providers need to know when a patient needs surgical therapy or needs a combination of surgical and medical therapy based on duration of genital lesions, immune status, size of lesion, location of lesion, distribution, and disease bulk.

Treatment is mainly classified as chemical, immunological, or surgical.

Chemical therapy

Podophyllin

This is an extract of podophyllum peltatum. It contains antimitotic agent podophyllotoxin which arrest the cell cycle in metaphase and leads to cell death.

It is administered topically as a single agent once or twice weekly and has limited success in clearing warts (20-50% clearance in three months). The solution is applied topically to a small area of skin, allowed to dry, and then washed off within six hours of application. Large area should not be treated in a single application because of potential neurotoxicity and pain when the area becomes necrotic.

It is very important not to apply to the cervix or vaginal epithelium because of risk of chemical burns. Main adverse effect is mild skin irritation to ulceration or pain depending on concentration and length of time agent was left on lesion. Also, this should not be used in pregnancy.

0.5% Podofilox

This is self-administered twice a day for three days followed by a four day rest period. It can be repeated up to four times. Self-administered podophyllotoxin solution or cream (0.5% and 0.15% respectively) has been compared to 25% podophyllin administered in a clinical setting, and self-administered podophyllotoxin was found to have greater efficacy and was more cost-effective than clinic based treatment. Recurrence within 12 weeks using both methods was 43%.

Trichloroacetic acid (80-90% concentration) or bichloroacetic acid

Trichloroacetic acid (TCA) physically destroys by protein coagulation. Clearance rate and side effects are similar to podophyllin. TCA requires repeated application and in contrast to podophyllin, can be used for internal lesions and during pregnancy. Apply petroleum jelly as barrier agent before application because it is caustic and can burn and inflict pain on normal unaffected skin.

5-Flurouracil epinephrine gel

This is a pyrimidine antimetabolite which interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid, which leads to cell death. Recurrence rates in patients with complete response to this therapy were 50-60% at three months.

Immune-mediated therapy

Imiquimod

This is a positive immune response modifier which acts by local cytokine induction. In one study, 72-84% of patients using 5% imiquimod cream topically had 40-70% complete clearance while few recurrences (5-19%) was noted. Imiquimod cream can weaken condoms and direct sexual contact is not recommended while using this medication. Imiquimod is not indicated for internal use. The approved regimen is the application of a 5% cream three times per week for 16 weeks and the application of a 3.75% cream daily for eight weeks.

Interferon alfa

Interferons have antiviral, antiproliferative, and immune stimulating effects. Primary systemic administration of interferon alfa eradicates genital warts in 25-80% of cases. It is administered intralesionally but not commonly used in daily clinical practice. Treatment dose is 1 million units per wart, two to three times weekly for up to eight weeks. Contraindicated in pregnancy.

Sinecatechins

This is a botanical drug product whose active ingredient kunecatechins is a mixture of catechins and other components of green tea. Sinecatechins inhibits HPV gene products E6 and E7, which reduce cell growth and inhibit proinflammatory enzymes and proteases, and has both antioxidant and immune enhancing activity. Sinecatechins is approved as a 15% ointment for topical treatment of external genital warts three times per day in persons 18 years and older.

Cidofivir and Bacillus Calmette

These are newer approach to management of genital warts that need more research.

Surgical excision

Surgical management is reserved in general for patients with extensive or bulky disease, lesions that do not respond to medical therapy, or multicentric disease involving the vagina, urethra, or anus. It consists of excisional and ablative procedures.

Cryotherapy with either liquid nitrogen or nitrous oxide destroys wart tissue via cell lysis. It is not recommended for use in the vagina because of the risk of vaginal perforation and fistula formation. An advantage is that it can be used during pregnancy. Electrotherapy requires anesthesia and operating room. The advantage is that in a single treatment, all warts could be eliminated. It can also be used inside the vagina.

Excisional procedures are recommended when malignancy cannot be ruled out. Laser (carbon dioxide) works by producing light energy, which is absorbed by water within the warty tissues leading to thermal damage and resultant ablation. The advantage is that it can be used to treat both cervical and vaginal warts and is preferred when the distribution of warts is extensive.

4. Complications

Bacterial and fungal superinfections are not uncommon. Candidal vaginitis has been described in as many as 10% of women with primary genital herpes, especially in diabetic women. Care must be taken to differentiate ulcerative whitish herpetic disease from yeast infection.

HSV complications in pregnancy

Genital herpes accounts for 1-2% of all cases of neonatal herpes. Cesarean delivery is recommended in mothers who have active genital lesion during labor. Of note, the presence of active genital lesion is not a good indicator of HSV viral shedding, thus the American College of Obstetricians and Gynecologist (ACOG) recommends that suppressive antiviral therapy be given to all women with a history of recurrent genital HSV in the last four weeks of pregnancy.

First episode infections have more severe consequences to the mother and baby. Thus, identification of women at risk for primary infection is paramount. Pregnant women may have widely disseminated infection with a high mortality rate (50%) and infection in the third trimester of pregnancy is associated with neonatal HSV infections, intrauterine growth restriction and prematurity.

Condyloma acuminata in pregnancy

Pregnancy is associated with a decrease in cell mediated immunity, which may lead to worsening of viral infection. During pregnancy, HPV shedding may increase, and condylomas may become so large as to impair normal delivery mechanically. The question of vertical transmission has been debated regarding anogenital warts, and more research is required to answer the question.

What is known and established in literature is that HPV can cause mucosal, conjuctival, or laryngeal disease in children. Juvenile-onset respiratory papillomatosis (JRP) is the most severe although rare outcome. Epidemiologic studies have linked JRP to a history of maternal anogenital warts. JRP lesions are most likely to carry HPV types 6 and 11, which are commonly found in the anogenital warts.

This raises the question regarding antenatal therapy or elective cesarean delivery as a means of reducing incidence of disease in children. Given the fact that treatment of visible lesions does not eliminate HPV virus, the potential for transmission most likely remains the same after treatment. In addition, more studies need to be conducted looking at the effect of antenatal treatment of genital warts on viral transmission to fetus. Cesarean delivery is indicated if genital warts obstruct the birth canal causing dystocia during a vaginal delivery. Large obstructing lesions can also avulse and bleed during the cause of parturition.

5. Prognosis and outcome

Recurrent genital herpes infection

The main morbidity of genital herpes is its frequent reactivation rate. Both subclinical and symptomatic reactivations are more common in HSV-2 infection than in HSV-1 infection. Recurrence rates of genital disease differ with the viral subtype. The 12 month recurrence rate after first episode for HSV-1 is 55%, and for HSV-2 is 90%. The median number of recurrence per year is <1 for HSV-1 and 2-5 for HSV-2.

Recurrence is preceded by a prodrome of tenderness, pain, and burning at the site of eruption that may last from two hours to two days. Infection can last for three to seven days, while lesion heals in 8-10 days. Patients who had severe primary genital herpes tend to have more frequent recurrences of longer duration. Recurrence has been linked to stress in women, and some women relate it to their menstrual cycle. Fever and systemic symptoms are uncommon. Symptoms are usually more severe in women compared to men. Viral shedding generally lasts an average of five days.

Patients with genital herpes infection should be counseled regarding safer sexual practices and offered testing for other sexually transmitted infections (including HIV). Prompt recognition and treatment reduce morbidity and mortality from HSV infections. Patients should be aware that HSV infection is life-long and, once established, there is no treatment to eliminate it. Antiviral therapy reduces or prevents complications.

HPV recurrence

HPV infections cannot be eradicated, but therapy will often rid the patient of visual warts. Recurrence is common, particularly with any immunosuppresive state. Spontaneous regression of HPV lesions sometimes does occur, and 20-30% of women may have regression of lesions within three months.

6. What is the evidence for specific management and treatment recommendations?

Xu, F, Sternberg, MR, Kottiri, BJ. "Trends in herpes simplex virus type 1 and 2 seroprevalence in the United States". JAMA. vol. 296. 2006. pp. 964.

(This data showed decline in HSV-2 seroprevalence, suggesting that the trajectory of increasing HSV-2 seroprevalence in the United States has been reversed. Seroprevalence of HSV-1 decreased, but the incidence of genital herpes caused by HSV-1 may be increasing.)

Patel, R, Alderson, S, Geretti, A. "European guideline for the management of genital herpes, 2010". International Journal of STD& AIDS. vol. 22. 2011. pp. 1-10.

(This paper gives a general but detailed over view of genital herpes and its management with levels of evidence to support choice and duration of antivirals.)

Brown, ZA. "The acquisition of herpes simplex virus during pregnancy". N Engl J Med. vol. 337. 1997. pp. 509.

(Brown et al. studied 7,046 pregnant women and 2% or more of susceptible women acquired HSV infection during pregnancy. Acquisition of infection with seroconversion completed before labor does not appear to affect the outcome of pregnancy, but infection acquired near the time of labor is associated with neonatal herpes and perinatal morbidity.)

Chilukuri, S, Rosen, T. "Management of acyclovir resistant herpes simplex virus". Dermatol Clin. vol. 21. 2003. pp. 311.

(This paper gives detailed management of acyclovir-resistant herpes simplex virus. The treatment protocol used includes initiation of acyclovir orally, and if little or no response, the dose is titrated upwards. If there is no improvement after five to seven days of therapy, authors recommend to reculture patient to ascertain its HSV and then switch to IV foscarnet. Vidarabine is reserved for when all therapies fail.)

Gupta, R, Warren, T, Wald, A. "Genital herpes". Lancet. vol. 370. 2007. pp. 2127.

(This seminar summarizes the epidemiology and pathogenesis of HSV and presents approach for the assessment, treatment, and prevention of genital herpes.)

Langenberg, AG, Corey, L, Ashley, RL. "A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV vaccine study group". N Engl J Med. vol. 341. 1999. pp. 1432.

(In this study, the rates of new HSV-1 and HSV-2 infections were 1.6 and 5.1 cases per 100 person-years respectively. Previous HSV-1 infection did not reduce the rate of HSV-2 infection, but it did increase the likelihood of asymptomatic seroconversion. Among sexually active adults, new genital HSV-1 infections are as common as new oropharyngeal HSV-1 infections.)

Corey, l, Adams, HG, Brown, ZA, Holmes, KK. "clinical manifestations, course, and complications". Ann Intern Med. vol. 98. 1983. pp. 958.

(Symptoms of genital herpes were more severe in women than in men. Primary first-episode genital herpes patients tend to present with bilaterally distributed lesions compared to small vesicular unilateral lesions in recurrent episodes. Nearly 25% of recurrent episodes were asymptomatic.)

Forcier, M, Musacchio, N. "An overview of human papillomavirus infection for the dermatologist: disease, diagnosis, management, and prevention". Dermatol Ther. vol. 23. 2010. pp. 458-76.

(Concise overview of HPV infections.)

Banhidy, F, Acs, N, Puho, E H, Czeizel, AE. "Birth outcomes among pregnant women with genital warts". Int J gynaecol obstet. vol. 108. 2010. pp. 152-60.

Ault, KA. "Epidemiology and natural history of human papillomavirus infections in the female genital tract". Infect Dis Obstet Gynecol. vol. 40470. 2006. pp. 1-5.

Manhart, LE, Koutsky, LA. "Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia". A meta-analysis. Sex Transm Dis. vol. 29. 2002. pp. 725.

Workowski, KA, Berman, S. "Sexually transmitted disease treatment guidelines,2010". MMWR Recomm Rep. 2010. pp. 59.

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