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Chapter 9: Genital Ulcers

ETIOLOGY/EPIDEMIOLOGY

The most common cause of genital ulcerative disease worldwide is herpes simplex virus (HSV), followed by the chancre of primary syphilis. Two types of HSV have been identified: HSV-1 and HSV-2. Most cases of genital herpes are caused by HSV-2 but an increasing proportion of infections in some populations are due to HSV-1. Although 16% of adults in the U.S. are HSV-2 seropositive, only 10-20% of persons have a history of recognizable genital herpes infection. Lymphogranuloma venereum (LGV), caused by C. trachomatis serovars L1, L2 or L3, can cause genital ulcers, particularly when the infection is acquired through vaginal intercourse. Other causes of ulcerative genital lesions including Haemophilus ducreyi (chancroid) and granuloma inguinale (Donovanosis), are seen more rarely in the U.S., but should be considered among men who have sex with men (MSM) and those who have traveled to endemic regions of the world, including the Caribbean. In 10 to 20% of genital ulcers, a causative agent cannot be identified despite extensive laboratory testing. This chapter will describe the clinical manifestations and management of common causes of genital ulcerative disease in the U.S.

CLINICAL MANIFESTATIONS

Historical information may be of value in determining the probable etiology of genital ulcers, including the exploration of sexual networks, travel, and sexual practices. However, in the absence of definitive vesicles that indicate genital herpes, it is critical to note that the microbiologic etiology of genital ulcers cannot be determined by history and physical examination. Genital herpes lesions often evolve or present de novo as a single ulcer lacking vesicles, and can easily be mistaken for primary syphilis, in particular.

HSV

In primary genital herpes, lesions typically develop an average of 4 to 7 days after exposure. [Image 1, Image 2, Image 4] After healing of the initial lesions, recurrent lesions often appear within 1 to 4 months. Most HSV transmission occurs during periods of subclinical genital shedding. This occurs when HSV is detectable on genital mucosa without clinically apparent visible lesions consistent with herpes. The first year after a primary herpes infection is classically the period of highest risk of asymptomatic viral shedding, particularly for disease due to HSV-2.  The subsequent pattern of recurrence for genital HSV-2 infection varies widely, but averages 4 to 7 episodes per year. 

Research suggests that while those with asymptomatic HSV-2 infection shed virus less frequently than those with symptomatic infection, ongoing intermittent viral shedding is generally the rule rather than the exception for all infected people. Patients who are diagnosed with herpes should be counseled about the possibility of subclinical shedding, the role of condoms to reduce transmission during asymptomatic periods, suppressive antiviral therapy (both to reduce the rate of clinical recurrences and to reduce transmission to uninfected sex partners), and abstinence during recurrences.

If the patient clearly gives a history of multiple vesicular lesions that have evolved over a period of days and are often painful, genital herpes should be strongly suspected. In primary herpes, painful lymphadenopathy and occasionally signs and symptoms consistent with a viral syndrome that include fevers and myalgias often accompany vesicular lesions. In patients who have lesions that are not vesicular but ulcerative, it is important to obtain a careful description of the evolution of the lesions. If the patient can describe previous vesicular lesions that became ulcerative, genital herpes remains the most likely diagnosis. A history of recurrent lesions in the same area, local neuralgias or hyperesthesia that preceded the outbreak, or exposure to a partner with genital herpes also strongly supports the diagnosis of genital herpes. Recurrent genital HSV lesions are not usually associated with lymphadenopathy or systemic symptoms.

HSV Images

Image 9-1. Granulating ulcer
Image 1.
Granulating ulcer on right labia characteristic of HSV
Image 9-2. HSV infection
Image 2.
Severe primary HSV infection with penile edema
Image 9-4. Recurrent HSV lesions
Image 4.
Recurrent HSV lesions showing vesicles and ulcer.

 

Syphilis

The incubation period for primary syphilis is 10 to 90 days, with most lesions appearing within 2 to 6 weeks. [Image 3] The primary syphilitic lesion will heal, even without treatment, and is often followed by the rash of secondary syphilis [Image 7, Image 9] in 1 to 4 months.  

Painless genital lesions (known as chancres) that generally precede the development of a systemic rash are more suggestive of syphilis.  The painless nature of chancres enhances the likelihood of transmission.  They appear, on average, three weeks after exposure, are generally 0.5-1.5 cm in diameter, have a clear base with a raised, indurated margin accompanied by mild to moderate regional lymphadenopathy.  Chancres are located on the penis in men and on the labia or cervix of women.  Because of the visible character of chancres on male genitalia, men may be more likely than women to present for clinical care in the primary stage of infection.   Chancres tend to heal spontaneously within three to six weeks even in the absence of treatment. 

The secondary stage of syphilis is generally accompanied by systemic manifestations of disseminated disease, including low-grade fever, malaise, sore throat and rash.  The rash, while often overlooked by the patient and provider, is the most characteristic feature of secondary syphilis.  It can take virtually any form (though generally absent of vesicular lesions) but is classically diffuse, symmetric with macular and popular eruptions throughout the trunk and extremities including the palms and soles.  Other manifestations in this stage of syphilis include generally painless and nontender lymphadenopathy commonly present in posterior cervical, epitrochlear, axillary and inguinal regions.  Condyloma lata, a term to describe large, raised, whitish lesions in warm moist areas (frequently perineum or anal) are a common manifestation of this stage of syphilis [Image 8]. Mucous patches may be found on the tongue [Image 7].  Patients may also experience alopecia over the scalp or eyebrows.  Periosteal inflammation that is asymptomatic can also occur and usually resolves with treatment.  Iritis, uveitis, glomerulonephritis or nephrotic syndrome can  also occur, given the circulating immune complexes.

Syphilis Images

Image 9-3. Syphilitic chancre
Image 3.
Syphilitic chancre
Image 9-6. Treponema pallidum<br />
Description:  Spirochetes seen with darkfield microscope
Image 6.
Treponema pallidum spirochetes seen with darkfield microscope
Image 9-7. Mucous patches
Image 7.
Mucous patches on tongue in secondary syphilis
Image 9-8. Secondary Syphilis
Image 8.
Condyloma lata lesions of secondary syphilis
Image 9-9. Rash of secondary syphilis involving palms and feet
Image 9.
Rash of secondary syphilis involving palms and feet
 

 

Chancroid

Chancroid has an incubation period of 1 to 14 days [Image 5]. Early infection with H. ducreyi tends to present with painless papules and pustules. Patients rarely recall experiencing this stage but will generally endorse symptoms associated with the evolution of ulcers from pustules within the weeks following acquisition. Ulcers tend to be painful, bleed easily and are characterized with ragged edges. As many as 10-40% of patients with chancroid also have inguinal lymphadenopathy or buboes.

LGV

The primary lesions of LGV develop within 3 to 21 days after exposure. LGV can present as a papule, an ulcer, a herpetiform lesion or urethritis. The coronal sulcus is the most common site for an LGV ulcer in men. The posterior vaginal wall, the fourchette, posterior lip of the cervix and vulva are most often affected in women. LGV can also present as cervicitis in women.

Proctitis or proctocolitis are common manifestations of LGV, particularly among MSM [Image 10]. The secondary stage of LGV is characterized by painful swelling of the inguinal lymph nodes and is commonly the reason patients seek medical care. The inguinal bubo is generally unilateral and is often accompanied by constitutional symptoms including fever, thought to be secondary to chlamydia bacteremia.

Image 9-5. Chancroidal ulcer
Image 5.
Chancroidal ulcer showing purulent appearing base
Image 9-10. Proctitis due to C. trachomatis
Image 10.
Proctitis due to C. trachomatis

 

Granuloma Inguinale/Donovanosis

Typical features of infection secondary to Klebsiella granulomatis (thought to be the causative organism responsible for infection) include the finding of a firm papule or subcutaneous nodule that later ulcerates.  There are four common types of donovanosis (STD, 4th Edition, Chapter by Nigel O’Farrell):

  1. Ulcerogranulomatous (most common variant): nontender, fleshy, exuberant, single or multiple beefy-red ulcers
  2. Hypertrophic: ulcer/growth with a raised, irregular edge
  3. Necrotic: deep, foul-smelling ulcer causing tissue damage
  4. Sclerotic: extensive fibrous formation and scarring

Lymphadenopathy is not a common finding in donovanosis. 


Examination

The clinical characteristics of genital ulcers are outlined in Table 9-1. It is important to bear in mind that more than one pathogen may occur simultaneously in the same ulcer.

Table 9-1

Diagnostic Characteristics and Treatment of Sexually Transmitted Genital Ulcers
  Primary HSV Recurrent HSV Syphilis Chancroid LGV
Primary Lesion Vesicle, papules, ulcers, typically bilateral Grouped vesicles, papules, ulcers, typically unilateral Ulcer, papule Ulcer, papule Papule, pustule, ulcer
Border Erythematous, "punched out" Erythematous "punched out" Sharply demarcated Violaceous, undermined Variable
Depth Superficial Superficial Superficial Excavated Superficial
Base Red and smooth Red and smooth Red and smooth Yellow to gray exudate Variable
Secretion Serous Serous Serous Purulent to hemorrhagic Variable
Number of Lesions Bilateral, multiple, extensive lesions may coalesce Usually unilateral, multiple clustered lesions Usually one; occasionally multiple Usually one to three; may be multiple Usually one
Genital Distribution Women: labia (bilateral), cervix, urethra, perianal
Men: penis, urethra, rectum
Usually unilateral; labia, penis, scrotum, buttocks, perianal Vulva, penis, anal, perianal, oral Penis, vulva Urethra, cervix, rectum
Induration None None Firm Rare; usually soft None
Pain Common Common, less severe Rare Often Variable
Itching Common Common Rare Rare Rare
Lymph Nodes Tender, firm, bilateral inguinal adenopathy Lymphadenopathy uncommon, unilateral Nontender, firm, enlarged Tender, enlarged, may suppurate Inguinal and femoral lymphadenopathy; tender, may suppurate
Incubation Period 2-14 days Recurrence within 6-9 months of primary infection 10-90 days 1-14 days 3-21 days
Time Course 21 days 7-10 days 2-3 weeks 2-3 weeks 1-2 weeks
Diagnostic Test* Cell culture and PCR are preferred for diagnosis of HSV in a patient who presents with genital ulcer(s) or mucocutaneous lesion(s). Cell culture and PCR of genital ulcer(s) or mucocutaneous lesion(s). Also, virologic and type-specific serologic tests for HSV are available in most clinical settings that care and manage individuals at risk for STDs. Darkfield examinations remains the definitive method for diagnosing early syphilis. Nontreponemal tests (VDRL and RPR) and treponemal tests (FTA-ABS, TP-PA, various EIAs and chemiiluminescence immunoassays). The use of one type of serologic test is insufficient for diagnosis. Culture of H. ducreyi on special media that is not widely available from commercial sources. Currently, no FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and have conducted a CLIA verification study. Genital and lymph node specimens (i.e., lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. NAATs for C. trachomatis are not FDA-cleared for testing rectal specimens, although some laboratories have performed the CLIA validation studies that are needed to provide results for clinical management. Although not widely available, molecular procedures (PCR) can differentiate LGF from non-LGV C. trachomatis. Finally, chlamydia serology (complement fixation titers >1:64) can support the diagnosis of LGV in the appropriate clinical context.
*Check out the Clinical Services Directory by state at: http://www.ncsddc.org/

Inguinal lymphadenopathy often accompanies genital ulceration and is of some help in distinguishing the various types of genital ulcers. Patients with primary herpes generally have very painful adenopathy, patients with chancroid and LGV often have tender but less painful adenopathy, and patients with syphilis usually have painless adenopathy. These distinctions, however, do not permit definitive diagnosis.

DIAGNOSIS

Figure 9-1 provides an algorithm for the diagnosis and management of genital ulcers (Reproduced with the permission of the Sylvie Ratelle STD/HIV Prevention Training Center of New England).

Figure 9-1: Genital Ulcer Disease (Male/Female) — Darkfield Unavailable

Herpes Simplex Virus

The vast majority of cases of HSV can usually be diagnosed with a history combined with a physical exam.  Laboratory diagnosis of genital herpes most commonly utilizes either viral culture or polymerase chain reaction (PCR).  Increasingly, PCR has emerged as the best modality for testing individuals with ulcers suspicious for genital HSV and is four times more sensitive than viral culture.  Both of these methods offer the ability to sub-type HSV-1 and HSV-2.  Approved late in 2011, a molecular nucleic acid amplification assay (IsoAmp) detects HSV from either genital or oral lesions but is limited in its ability to distinguish between HSV-1 and HSV-2 infection. 

Other methods of testing include antigen tests that generally have a sensitivity similar to culture.  Of the non-culture tests, only the direct fluorescent antibody (DFA) test distinguishes HSV-1 from HSV-2.  Cytology (Pap, Tzanck preparations) are older and less sensitive tests that no longer play a role in clinical management.  Finally, serologic tests (i.e. type-specific glycoprotein G (gG)-based assays) are commercially available (for example, HerpeSelect ELISA) and can be helpful in determining the etiology of genital ulcers and when screening for unrecognized HSV infection.  There are several limitations of HSV serology including the inability of the test to diagnose a lesion, to predict whether an individual has had or will develop symptoms, and to determine how long an individual has been infected and whether she/he is likely to experience subclinical shedding.  Interpreting serologic results can be challenging, so providers are encouraged to consider using the assays in the following situations (per CDC STD Treatment Guidelines at http://www.cdc.gov/std/treatment). 

  • Signs or symptoms consistent with genital herpes without laboratory confirmation
  • HIV infection
  • Request for STD evaluation
  • MSM at high risk for HIV acquisition

An increasing proportion of genital ulcerative infections are attributed to HSV-1, particularly among some sub-populations, including some college-age students, women who have sex with women, and MSM. Genital HSV reactivation, both symptomatic and asymptomatic, occurs less frequently with HSV-1 than HSV-2 infection. Approximately 50% of patients with genital HSV-1 will experience a recurrent episode in the first year following primary infectionvmptomatic and asymptomatic, occurs less frequently with HSV-1 than HSV-2 infection. Approximately 50% of patients with genital HSV-1 will experience a recurrent episode in the first year following primary infection.

Syphilis Testing

Darkfield examination (DFA-TP) has traditionally been the gold standard for diagnosing syphilis as the cause of suspicious genital ulcerative lesions [Image 6]. However, few clinics with the necessary equipment and skill in this practice remain, leaving serology as the usual diagnostic approach. Traditionally, the diagnostic workup began with non-treponemal tests (RPR or VDRL), followed by confirmation with treponemal testing (typically, T. pallidum particulate antigen (TPPA) or fluorescent treponemal antibody absorbed (FTA-ABS). Increasingly, the approach in the U.S. is now to first send serum for a specific treponemal serologic test in the form of an enzyme immunoassay (EIA) or chemiluminescence immunoassays (CLIA), so called "reverse sequence" testing (see algorithm 9-1 below). If this test is positive, reflexive testing of the RPR or VDRL is done with quantification of the titer if it is reactive to guide in treatment decisions. The following algorithm illustrates the recommended approach to diagnostic testing using syphilis serology.

Algorithm 9-1: Recommended Approach to Diagnostic Testing Using Syphilis Serology

algorithm illustrating syphilis testing

Chancroid

The gold standard method for diagnosing chancroid relies on the identification of H. ducreyi on special culture media .  Although not FDA approved, PCR for H. ducreyi is available and utilized by labs that have undergone CLIA verification.  Otherwise, per the CDC (http://www.cdc.gov/std/treatment), the following criteria fulfill probable diagnosis of chancroid:

  • One or more painful genital ulcers
  • No evidence of T. pallidum infection by darkfield examination or by serologic test for syphilis performed at least 7 days after onset of ulcers
  • Clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid
  • A test for HSV performed on the ulcer is negative

LGV

The diagnosis of LGV relies largely on clinical suspicion combined with pertinent epidemiology and the exclusion of other etiologies.  Culture, direct immunofluorescence and nucleic acid detection are available for genital swab specimens.  NAATs for C. trachomatis, while not FDA cleared, can be performed in CLIA validated settings.  Moreover, chlamydia serology (complement fixation titers > 1:64) can aid in the diagnosis of LGV, but this testing is not standardized or widely utilized.

Granuloma Inguinale

K. granulomatis is exceptionally challenging to culture from a lesion.  Instead, the diagnosis of granuloma inguinale relies on the identification of dark-staining Donovan bodies (rod shaped oval organisms) on tissue smears or biopsy.  There are no serologic tests commonly available.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of ulcers restricted to the genital area in sexually active patients include the etiologic agents discussed above, as well as fixed drug reactions, local trauma (e.g., zipper), vulvovaginal candidiasis or other causes of inflammatory vulvitis, excoriation of non-ulcerative skin lesions (e.g., scabies, staphylococcal or streptococcal infection), and squamous cell carcinoma.

Unlike infectious ulcerations, which have incubation periods of days to weeks, traumatic ulcers usually develop quickly (0 to 24 hours) after sexual intercourse. Medications that are associated with a fixed drug reaction include the tetracyclines, sulfonamides, metaqualone (Quaalude) and, less often, phenolphthalein laxatives and barbiturates. In addition, some topical therapies used to treat vaginal infections, including boric acid and paromomycin cream, can cause genital ulceration.

Outbreaks of genital cellulitis have been attributed to methicillin-resistant Staphylococcal aureus (MRSA) infection; while not always associated with a classical picture of genital ulceration, these infections can present with severe folliculitis and local abscess formation that can occasionally proceed to an ecthyma-like picture, prompting consideration of classic genital ulcer disease.

A pertinent question is whether or not the ulcers are restricted to the genital area. Ulcerative processes involving both genital and nongenital sites suggest nonvenereal origin, such as psoriasis, lichen planus, Behcet's disease, dermatitis herpetiformis, erythema multiforme, apthous ulcerations, pemphigus, or pemphigoid.

TREATMENT

For a more detailed discussion of these regimens and other treatment considerations, please refer to the CDC STD Treatment Guidelines at http://www.cdc.gov/std/treatment/.

In order to effectively treat genital ulcers, a specific diagnosis must be established.  In addition to the primary infections, secondary infection with other bacteria may occur, especially with chancroid, and must also be treated. Treatment of the secondary infection may consist simply of frequent application of warm compresses to remove exudate and necrotic material; alternatively topical or systemic antibacterial medication may be required for serious bacterial superinfection, as is occasionally seen with S. aureus.

Herpes Simplex Virus

Systemic anti-viral therapy should be offered to patient for both initial outbreaks and for recurrent episodes of genital herpes. To be effective, therapy should be started at the onset of symptoms or during the prodrome (in the latter case, prompt initiation of antiviral therapy can occasionally abort the appearance of clinical outbreaks).

Counseling is one of the most challenging aspects of managing patients with genital herpes, or those whose sex partner has genital herpes. The following are standard counseling messages for persons with genital herpes:

  • Persons who have genital herpes should be educated concerning the natural history of the disease, with emphasis on the potential for recurrent episodes, viral subclinical shedding, and the attendant risks of sexual transmission.
  • Persons experiencing a first episode of genital herpes should be advised that suppressive therapy is available and effective in preventing symptomatic recurrent episodes and that episodic therapy often is useful in shortening the duration of recurrent episodes.
  • All persons with genital HSV infection should be encouraged to inform their current sex partners that they have genital herpes and to inform future partners before initiating a sexual relationship.
  • Sexual transmission of HSV can occur during asymptomatic periods. Subclinical shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.
  • All persons with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.
  • The risk for HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person. Episodic therapy of recurrences does not reduce the risk for transmission and its use should be discouraged for this purpose among persons whose partners might be at risk for HSV-2 acquisition.
  • Infected persons should be informed that male latex condoms, when used consistently and correctly, might reduce the risk for genital herpes transmission.
  • Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of the asymptomatic partners of persons with genital herpes is recommended to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists.
  • The risk for neonatal HSV infection should be explained to all persons, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy and those who will care for their newborn infant about their infection. Pregnant women who are not known to be infected with HSV-2 should be advised to abstain from sexual activity with partners who have genital herpes during the third trimester of pregnancy. Similarly, pregnant women who are not known to be infected with HSV-1 should be counseled to avoid genital exposure to HSV-1 during the third trimester (e.g., oral sex with a partner with oral herpes and vaginal intercourse with a partner with genital HSV-1 infection).
  • Asymptomatic persons diagnosed with HSV-2 infection by type-specific serologic testing should receive the same counseling messages as persons with symptomatic infection. In addition, such persons should be educated about the clinical manifestations of genital herpes.
  • When exposed to HIV, HSV-2 seropositive persons are at increased risk for HIV acquisition. Patients should be informed that suppressive antiviral therapy does not reduce the increased risk for HIV acquisition associated with HSV-2 infection.

Comprehensive information on counseling persons with genital herpes can be found at www.ashastd.org

Currently available pharmacotherapy, while well tolerated, has some limitations.  Recent data demonstrates that subclinical genital HSV reactivation may continue to occur despite administration of high-dose (versus standard dose) antiviral therapy (Johnston C, Lancet 2012). 

Clinical trials are underway to elucidate the potential role of anti-retroviral drugs used in pre-exposure prophylaxis in the prevention of HSV, especially among individuals at high risk for HIV acquisition.  One trial demonstrated that pericoital vaginal application of tenofovir gel provided a 51 percent protective effect against the acquisition of HSV-2 (Abdool Karim Q et al. Science, 2010).  Additional data on this finding are anticipated in the near future.

Initial episodes Genital HSV  (per CDC Treatment Guidelines, 2010)

Recommended Regimens*

Acyclovir 400 mg orally three times a day for 7–10 days

OR

Acyclovir 200 mg orally five times a day for 7–10 days

OR

Famciclovir 250 mg orally three times a day for 7–10 days

OR

Valacyclovir 1 g orally twice a day for 7–10 days

*Treatment can be extended if healing is incomplete after 10 days of therapy.

Suppressive (prophylactic) therapy for Recurrent Genital Herpes

Suppressive antiviral therapy reduces the recurrence of genital herpes by 70-80% in patients who experience recurrences. Moreover, a study of HSV-2 discordant heterosexual couples showed an approximately one-half reduction in the rate of HSV-2 transmission when the infected partner took daily valacyclovir (500 mg) (Corey L et al. NEJM, 2004).

Recommended Regimens*

Acyclovir 400 mg orally twice a day

OR

Famiciclovir 250 mg orally twice a day

OR

Valacyclovir 500 mg orally once a day*

OR

Valacyclovir 1 g orally once a day

* Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in patients who have very frequent recurrences (i.e., ≥10 episodes per year).

Episodic Therapy for Recurrent Genital Herpes

Persons who experience recurrent episodes of genital herpes who may not opt or be eligible for suppressive therapy may initiate therapy within one day of onset of genital lesions or viral prodrome.  These patients should be provided either with a supply of anti-viral medication or prescription with instructions to initiate therapy as early as possible with onset of symptoms.

Recommended Regimens

Acyclovir 400 mg orally three times a day for 5 days

OR

Acyclovir 800 mg orally twice a day for 5 days

OR

Acyclovir 800 mg orally three times a day for 2 days

OR

Famciclovir 125 mg orally twice daily for 5 days

OR

Famciclovir 1000 mg orally twice daily for 1 day

OR

Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days

OR

Valacyclovir 500 mg orally twice a day for 3 days

OR

Valacyclovir 1 g orally once a day for 5 days

Special regimens for HIV-infected persons

Because immunocompromised persons may have prolonged or severe episodes of herpes, treatment may need to be more intense, and suppressive therapy is often beneficial.  Moreover, HSV shedding is increased in frequency, duration and intensity (as measured by quantitative HSV-2 PCR assay) in HIV-infected patients.

Recommended Regimens for Daily Suppressive Therapy in Persons with HIV

Acyclovir 400–800 mg orally twice to three times a day

OR

Famciclovir 500 mg orally twice a day

OR

Valacyclovir 500 mg orally twice a day

Recommended Regimens for Episodic Infection in Persons with HIV

Acyclovir 400 mg orally three times a day for 5–10 days

OR

Famciclovir 500 mg orally twice a day for 5–10 days

OR

Valacyclovir 1 g orally twice a day for 5–10 days

Pregnant Women

The safety of systematic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been established, but they are used commonly in clinical practice. Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester and the drug tends to be well tolerated. Common clinical practice is to prescribe anti-HSV therapy (commonly acyclovir or valacyclovir) to pregnant women at 36 weeks gestation that have a history of recurrent genital HSV. Less is known about the effects of prenatal exposure to valacyclovir and famciclovir.

Antiviral Resistance

HSV resistance is a consideration among patients who fail to improve with treatment with any of the standard recommended agents or who have frequent outbreaks despite daily suppressive therapy; however, clinical data do not indicate that this is a common event, and other explanations, including low adherence to medication, should be considered. Given that the usual antivirals used in HSV infection are mediated by viral thymidine kinase, HSV resistance to acyclovir generally indicates resistance to valacyclovir and famciclovir. Consultation with an infectious diseases specialist is recommended to help coordinate resistance testing and trial of alternate anti-viral agents including foscarnet or cidofovir. These are parenteral options that require close supervision.

Syphilis

Penicillin remains the treatment of choice for syphilis. The formulation (i.e., benzathine, aqueous procaine, or aqueous crystalline), dosage and length of therapy depend on the stage of infection. Practitioners should note that the correct formulation of penicillin to use is Bicillin L-A, and not Bicillin C-R, which has been given erroneously for this purpose. Because tetracycline is not a recommended first line therapy, it is extremely important to counsel the patient about adherence to the regimen if it is used since omission of only a few doses or slight shortening of therapy can significantly increase the failure rate. All persons with syphilis should have HIV testing performed at the time of diagnosis, with repeat HIV testing in 3 months to ensure that recent acquisition has not occurred. The failure rate.

Primary and Secondary Syphilis

Recommended Regimen for Adults, HIV uninfected and HIV infected*

Benzathine penicillin G 2.4 million units IM in a single dose

*Counsel patient about the possibility of Jarisch-Herxheimer reaction. 

Patients diagnosed with syphilis who presents with signs or symptoms suggestive neurologic disease (e.g., meningitis, hearing loss) or ophthalmic disease (e.g., uveitis, iritis, etc.) should undergo lumbar puncture for CSF evaluation, ocular examination and ocular slit-lamp evaluation.  (See section on Neurosyphilis.)

Clinical and serologic follow up for primary and secondary syphilis should occur at 6 months and 12 months post-treatment, or more frequently, as clinically indicated; in addition, persons co-infected with HIV should be assessed on a quarterly basis after diagnosis to ensure adequate response.  Adequate response to therapy includes a fourfold drop in nontreponemal titer.  Persons who do not exhibit this response may have been reinfected or, more rarely, failed treatment.  Because it is challenging to distinguish reinfection from treatment failure, practitioners should pursue CSF analysis.  If CSF examination is unremarkable, these persons should undergo re-treatment (consisting of benzathine penicillin G 2.4 million units IM for 3 weeks) and repeat evaluation for HIV. 

Latent Syphilis

Latent syphilis is divided into early latent syphilis and late latent syphilis.  Those who acquired syphilis in the preceding year have early latent syphilis, as documented by any of the following: 

  • Seroconversion in the preceding year or a minimum of a fourfold increase in titer of nontreponemal titer
  • Unequivocal symptoms of primary or secondary syphilis
  • A sex partner during the past year documented to have primary, secondary or early latent syphilis

If a patient has a reactive titer and fulfills none of the above criteria, then a diagnosis of late latent syphilis or syphilis of unknown duration applies. All patients diagnosed with latent syphilis should undergo HIV testing and a clinical examination that includes thorough oral and anogenital mucosal evaluation.

Moreover, individuals diagnosed with latent syphilis with any of the following should undergo lumbar puncture for CSF evaluation:

  • Neurologic or ophthalmic signs or symptoms
  • Evidence of active tertiary syphilis (e.g., aortitis and gumma)
  • Serologic treatment failure
Recommended Regimens for Adults
Early Latent Syphilis

Benzathine penicillin G 2.4 million units IM in a single dose

Late Latent Syphilis or Latent Syphilis of Unknown Duration

Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

Neurosyphilis

Cerebrospinal fluid (CSF) laboratory abnormalities are common among individuals with syphilis, particularly with early syphilis and in those with concomitant HIV infection, including among those without neurological findings. Lumbar puncture is recommended for persons who show signs or symptoms of central nervous system dysfunction. These signs include motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, ocular/ophthalmologic signs, or signs and symptoms of meningitis (including chronic headache). Notably, the most recent CDC STD Treatment Guidelines (2010) do not recommend routine lumbar puncture for patients with HIV and syphilis, regardless of CD4 count and quantitative non-treponemal test titer, unless CNS signs or symptoms are present. Some experts continue to recommend routine lumbar puncture in the HIV-infected patient, particularly when CD4 count is <350 cells/mL and/or a serum RPR titer of >1:32. Data to support CSF evaluation in the asymptomatic patient with regard to long-term improvements in clinical outcome are lacking.

(See Syphilis among HIV-Infected Persons).

Recommended Regimen

Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10–14 days

If compliance with therapy can be ensured, the following alternative regimen might be considered.

Alternative Regimen

Procaine penicillin 2.4 million units IM once daily

PLUS

Probenecid 500 mg orally four times a day, both for 10–14 days

Penicillin Allergy

Although limited experience suggests that ceftriaxone may be considered for treatment of neurosyphilis among those with penicillin allergy, there remains a low risk of cross reactivity.  Therefore, among those patients who endorse serious penicillin allergies, skin testing should be pursued and, as necessary, penicillin desensitization performed in consultation with a specialist.

Syphilis among HIV-Infected Persons

Available data does not support any utility or enhanced efficacy with extended durations of antimicrobial therapy for syphilis among HIV infected persons.; these patients should receive standard regimens, including single-dose penicillin for early syphilis (including early latent syphilis).  Follow up testing should occur at 3, 6, 9, 12 and 24 months after therapy for those who are HIV infected.   

Evidence of neurologic invasion with T. pallidum is more common in HIV-infected persons with a CD4 count of <350 cells/mL and/or an RPR titer of >1:32. However, data to support that routine lumbar puncture in such patients is associated with a higher rate of favorable clinical outcomes are lacking; thus, the CDC recommends lumbar puncture only when neurological signs or symptoms are present (or if treatment failure is present and the CNS is under consideration as a reservoir).

Syphilis during Pregnancy

Syphilis screening should be performed at the first prenatal visit for all women.  Furthermore, in settings where community prevalence for syphilis is high or among high risk patients, repeat syphilis testing should occur in the third trimester and again at delivery.  Serologic titers should be repeated in the third trimester, between 28-32 weeks’ gestation and at delivery, depending on stage of disease.  Most women will deliver prior to optimal serologic response, so close clinical follow up is essential.  

Penicillin is the treatment of choice for syphilis among pregnant women (tetracyclines are contraindicated).  Pregnant patients who report an allergy to penicillin should undergo desensitization, in consultation with a specialist, and subsequent treatment with penicillin.   

Recommended Regimen*

Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection.

*Some evidence support additional therapy (for example, a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for those with primary, secondary, or early latent syphilis).  Providers should consult high risk obstetricians and infectious diseases specialists to plan and closely coordinate care.

Chancroid

Recommended Regimens

Azithromycin 1 g orally in a single dose

OR

Ceftriaxone 250 mg intramuscularly (IM) in a single dose

OR

Ciprofloxacin* 500 mg orally twice a day for 3 days*

OR

Erythromycin base 500 mg orally three times a day for 7 days >

* Ciprofloxacin is contraindicated for pregnant and lactating women.

LGV

Recommended Regimen

Doxycycline 100 mg orally twice a day for 21 days

Alternative Regimen

Erythromycin base 500 mg orally four times a day for 21 days

Granuloma inguinale

Recommended Regimen

Doxycycline 100 mg orally twice a day for at least 21 days and until all lesions have completely healed

Alternative Regimens

Azithromycin 1 g orally once per week for at least 3 weeks and until all lesions have completely healed

OR

Ciprofloxacin 750 mg orally twice a day for at least 3 weeks and until all lesions have completely healed

OR

Erythromycin base 500 mg orally four times a day for at least 3 weeks and until all lesions have completely healed

OR

Trimethoprim-sulfamethoxazole one double-strength (160 mg/800 mg) tablet orally twice a day for at least 3 weeks and until all lesions have completely healed

FOLLOW-UP

Herpes Simplex Virus

Reexamination needed only if symptoms and signs do not resolve.

Syphilis

  • Nontreponemal titers should be checked at 6, 12 and 24 months after therapy for  HIV uninfected persons; CSF analysis should occur if titers increase fourfold, an initially high titer (>1:32) fails to decline fourfold or signs/symptoms attributable to syphilis develop
  • Nontreponemal titers should be checked at 3,6, 9, 12 and 24 months after therapy for those who are HIV infected
  • For those affected with neurosyphilis, practitioners should re-evaluate CSF every six months until the cell count is normal

All cases of confirmed syphilis should be reported to the state/local health department

Chancroid

Patients should be examined 3-7 days into therapy.  If clinical improvement is not apparent during this timeframe, the practitioner ought to consider an alternate diagnosis, treatment non-adherence or treatment failure due to antimicrobial resistance.

All cases of confirmed chancroid should be reported to the state/local health department.

LGV

Follow patients until signs and symptoms have resolved.

All cases of confirmed LGV should be reported to the state/local health department.

Granuloma Inguinale

Follow patients until signs and symptoms have resolved

MANAGEMENT OF SEX PARTNERS

Herpes Simplex Virus

  • Offer serologic testing to determine whether infection has already occurred
  • Counsel about the risk of transmission associated with subclinical shedding, and prevention modalities for the future

Syphilis

Contacts of patients with:

Early syphilis
  • Routine history
  • Physical examination for signs of syphilis
  • Syphilis serology and HIV testing
  • Administer empiric treatment for all contacts within the preceding 3 months
    (i.e., benzathine penicillin G 2.4 million U IM).
Late latent syphilis
  • Determine treatment based on syphilis serology.

Chancroid

  • Sex partners of patients diagnosed with chancroid should be examined and treated if they had sexual contact in the past 10 days prior to the patient's onset of symptoms

LGV

  • Routine STD exam, including testing for chlamydia and treated with a chlamydia regimen (azithromycin 1 gm orally single dose or doxycycline 100 mg orally twice a day for 7 days)for all contacts within the preceding 2 months

Granuloma Inguinale

  • Persons who have had sexual contact with a patient diagnosed with granuloma inguinale within 60 days before the onset of a patient's symptoms should have a clinical exam and empiric therapy

  SEQUELAE

  • HSV usually produces frequent recurrences, especially in the first year after infection, which may be physically and psychologically disabling.  Persistent and extensive cutaneous disease may occur in immunocompromised patients and, in pregnant women, may infect the neonate. Many individuals benefit from daily suppressive antiviral therapy. Because suppressive therapy is highly effective and nontoxic, providers should generally have a permissive stance on provision of suppressive therapy.
  • Untreated syphilis may produce a wide variety of complications, including tabes dorsalis, meningovascular infection, aortitis, gumma, and in pregnant women, spontaneous abortion and congenital syphilis.
  • Chancroid and LGV may lead to scarring and fibrosis, as well as fistula formation and chronic lymphadenitis.

References:

CDC. Discordant Results from Reverse Sequence Syphilis Screening ---Five Laboratories, United States, 2006--2010. MMWR 2011;60(05);133-137 [CDC MMWR]

Johnston C, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet. 2012 Feb 18; 379(9816):641-7 [PubMed]

Abdool Karim Q, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2012 Sep 3; 329(5996): 1168-74 [PubMed]

Corey L, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Eng J Med. 2004 Jan 1; 350(1):11-20 [PubMed]

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