Syphilis and HIV affect similar at-risk populations, including MSM, injection drug users, and people who exchange sex for drugs or money. Many patients are dually infected. For example, among primary and secondary syphilis cases reported to the Centers for Disease Control
and Prevention (CDC) in 2002, 25% occurred in HIV- infected persons. Among MSM, rates of syphilis and HIV coinfection may be as high as 60%.
Clinical and laboratory findings of syphilis can differ in HIV-infected patients in several ways. Multiple chancres and atypical or florid skin manifestations are more com- mon. HIV-infected patients are more likely to have chan- cres of primary syphilis at the same time as they manifest symptoms of secondary syphilis. In addition, more pro- tracted and malignant constitutional symptoms and greater organ involvement have been reported. Studies also have demonstrated that HIV-infected persons appear to have a greater risk of central nervous system involve- ment at all stages of syphilis infection. Neurosyphilis pre- sentations include meningitis and cranial nerve deficits, such as optic neuritis and deafness. Syphilitic uveitis, and particularly bilateral eye involvement, has been reported more frequently among HIV-infected patients than among those without HIV infection.
Because of the specific immune disturbances of B-cell function in HIV infection, antibody-based syphilis test- ing results in HIV-infected patients may be different in seemingly paradoxical ways (see Table 21–5). For exam- ple, HIV-infected patients in the early stages of HIV dis- ease who have syphilis tend to have higher titers of antibodies than HIV-uninfected patients with syphilis.
Also related to overexpression of B-cell activity in early HIV disease have been rare reports of falsely reactive nontreponemal test results. However, before defining a positive nontreponemal test as falsely positive (because a simultaneous treponemal test was negative), the clinician should repeat treponemal testing at least 1 week after the initial tests were performed. In cases where clinical sus- picion is high in the face of negative serologic test results, alternative tests (eg, biopsy of skin lesions with silver staining) may be useful to confirm the diagnosis.
The rate of decline of nontreponemal titers following successful therapy may also be influenced by early HIV disease. In a large, randomized, prospective study of patients with early syphilis, HIV-coinfected patients had
Table 21–5.Results of serologic syphilis testing in early- and late-stage HIV infection.
Early HIV versus non-HIV Late HIV or AIDS versus non-HIV Nontreponemal serologies Higher titers in patients with syphilis Occasional false-negative results in
(RPR, VDRL) Occasional false-positive results in patients with syphilis patients without syphilis
Nontreponemal titers Higher rate of serologically More frequent loss of prior reactivity post-treatment defined treatment failures
may be misleading due to slower decline of titers in patients who had meaningful clinical response RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratories test.
SEXUALLY TRANSMITTED DISEASES IN HIV-INFECTED PERSONS / 143 higher rates of serologically defined treatment failure,
although patients had equal clinical responses to therapy, suggesting that the expected decline in titer in HIV- infected patients may be delayed.
Standard indications for lumbar puncture in HIV- infected patients with syphilis are as follows: neurologic, ocular, or auditory symptoms or signs; latent syphilis of unknown duration or late latent syphilis (>1 year); tertiary syphilis; or suspected treatment failure. However, some authorities recommend lumbar puncture in all HIV- infected patients with syphilis. Surveillance data from the CDC suggest neurosyphilis is two to three times more common in HIV-infected patients than in uninfected patients. In one study of 326 patients, many of whom had early syphilis, 20% who underwent cerebrospinal fluid (CSF) analysis had neurosyphilis. Those with serum rapid plasma reagin (RPR) titers of 1:32 or higher were 7.6 times as likely to have laboratory evidence of central nerv- ous system involvement. A serum RPR titer of 1:32 or higher combined with a peripheral blood CD4 cell count of 350 cells/àL or lower conferred still higher odds of neu- rosyphilis in HIV-infected patients. Thus, a possible strat- egy to use in deciding whether to perform lumbar puncture in an HIV-infected syphilis patient without signs or symptoms of neurosyphilis might be to factor in serum RPR titer and a recent CD4 count.
The interpretation of CSF laboratory results in patients with syphilis and HIV infection requires careful consideration. Because mild pleocytosis (5–15 white blood cells [WBCs]/àL) can be attributed to HIV infec- tion alone, especially when CD4 counts are higher than 500 cells/àL, most experts would consider more than 20 WBCs/àL to be indicative of a secondary process (ie, syphilis). Elevated CSF protein concentrations are highly nonspecific findings in HIV infection and should not be used alone to make a diagnosis of neurosyphilis.
The CSF VDRL is not sensitive and may only be positive in 25–50% of patients with neurosyphilis.
In the absence of inflammation (<5 WBCs/àL), the sig- nificance of a reactive CSF VDRL result is even less clear (see Chapter 20).
If available, the CSF fluorescent treponemal antibody absorbed (FTA-ABS) test may be helpful, because it is likely to be positive in HIV-positive patients with neu- rosyphilis who have falsely negative CSF VDRL results, as well as in many patients without other evidence of neu- rosyphilis. A negative CSF FTA-ABS test essentially excludes neurosyphilis, but a positive CSF FTA-ABS is nonspecific and the diagnosis should not be made if this is the only abnormal CSF result. If CSF evaluation is equiv- ocal and neurosyphilis cannot be excluded, some experts would opt to treat patients for neurosyphilis while others would not. Such decisions are based in part on differing interpretations of the same data. Patient preferences, the likelihood of reliable follow-up, and other factors should also be incorporated in this decision-making process.
Similar treatment regimens are recommended for syphilis in both HIV-infected and uninfected patients;
however, because of concerns about a modest increase in risk for treatment failure, closer follow-up is recom- mended for HIV-infected patients at 3, 6, 9, 12, and 24 months. All patients with neurosyphilis, regardless of HIV status, require repeat CSF analysis at 6 months to document improvement.
Among HIV-infected patients who contract syphilis, several studies have reported that CD4 concentration drops and HIV plasma viral load rises from previous levels. In studies where changes were observed, both markers tended to return toward baseline levels follow- ing syphilis treatment. The magnitude of CD4 and viral load changes was largest in patients not receiving HAART, and most of those data are drawn from patients with CD4 concentrations greater than 200 cells/àL. In the medical care of HIV-infected patients, an increase in HIV viral load or decrease in CD4 T cell count should prompt an evaluation for syphilis infection. The effect of advanced syphilis on HIV disease progression or of early syphilis on patients with advanced AIDS is less well characterized.
Human Papillomavirus–associated Genital Warts & Malignancies
HPV-associated genital warts may be more extensive and more difficult to treat in HIV-infected patients.
Precancerous cervical lesions are much more common in HIV-infected women, and studies have reported up to ninefold increases in rates of cervical cancer in women with HIV. Among HIV-infected women with dysplasia, the severity of cervical disease correlates with the degree of immune compromise. Persistence of cervi- cal cancer-causing HPV strains is also more common in women with HIV infection and correlates with the level of immunosuppression.
Anal cancer is similar to cervical cancer; it is associated with the same HPV strains, characterized by a predictable progression through stages of dysplasia to frank neo- plasm, and can be detected by Pap smear techniques.
The prevalence of HPV in MSM is 60–75%, and the frequency of anal carcinoma in men with HIV infection is 80 times that of the general population and increases with decreasing CD4 count. Some experts recommend regular anal cytology at three-year intervals for all HIV- infected men regardless of history of receptive anal intercourse. Patients with abnormal anal Pap smears should be referred for anoscopy and biopsy. The role of the new HPV vaccine in management of HIV-infected patients is being investigated and is currently unclear.
Herpes Simplex Virus Type 2
Much recent work has focused on the role of genital ulcer disease caused by HSV-2 in the sexual transmission
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of HIV infection. HSV-2 infection (with symptomatic genital ulcers or with positive HSV-2 serology) in an HIV-uninfected sex partner of an HIV-infected person increases the likelihood that the HIV-negative partner will acquire HIV. Similarly, HSV-2 infection (with or without a history of symptomatic genital ulcers) in an HIV-infected person also increases the risk that he or she will transmit HIV to uninfected partners. The mecha- nism of enhanced HIV transmission between an asymp- tomatic HSV-2–positive, HIV-coinfected person and his or her HSV-2–negative, HIV-uninfected sex partner may be related to the increased HIV viral loads observed in HSV-2– and HIV-coinfected individuals.
HIV-infected, HSV-2–positive patients experience both more frequent symptomatic herpetic outbreaks and more frequent and prolonged asymptomatic HSV-2 viral shedding than persons without HIV infection. At pres- ent, determinants of HSV-2 asymptomatic viral shed- ding are unknown. Clinical trials of chronic suppressive anti–HSV-2 therapy to decrease HIV transmission (from a coinfected partner to an HIV-uninfected partner) and HIV acquisition (by an HIV-uninfected person with HSV-2 from his or her HIV-infected partner) are ongoing.
Symptomatic HSV-2 lesions are more common in HIV-infected persons and may be more severe, numer- ous, painful, prolonged, or atypical. In fact, chronic HSV-2 ulcers of more than 1 month’s duration are con- sidered an AIDS-defining illness in HIV-infected indi- viduals. HSV-2 ulcers appear frequently in the perianal area of HIV-infected people. In severely immunocom- promised patients, HSV-2 may present as hyperkera- totic verrucous lesions that mimic condylomata.
Disseminated lesions, refractory disease, and acyclovir- resistant HSV disease are also more common in patients with advanced HIV infection. Neurologic complica- tions of HSV-2 infection are rare, occur mostly in advanced AIDS, and develop rapidly. These complica- tions can include aseptic meningitis, sacral radiculopa- thy, and transverse myelitis. If herpes is unresponsive to acyclovir or related agents, viral culture with testing of isolates for thymidine-kinase mutations should be undertaken and treatment using foscarnet or cidofovir should be considered. In HIV-infected patients, the treatment of HSV-2 infection can require higher doses and prolonged courses of therapy.
Among HIV- and HSV-2–coinfected patients treated with high-dose acyclovir therapy to suppress HSV reacti- vation, plasma HIV-1 RNA levels at a given CD4 cell count were decreased by about half, suggesting that HSV reactivation is associated with increased HIV replication in vivo. HIV-infected individuals who develop HSV-2 recurrences have a median HIV viral load increase of 3.4- fold, and increased viral load is sustained for 30–45 days following appearance of genital lesions.
HSV-2 has been shown to upregulate HIV replica- tion at a cellular level. HSV-2 also likely plays a role in
determining the steady-state HIV viral load of patients in the early stages of HIV disease following acute infection (the so-called viral set-point). HSV-2–seropositive patients with acute HIV infection have been found to have higher HIV viral loads more than 1 year following their estimated date of HIV acquisition than HSV-2–seronegative patients. Because of the role of HSV-2 in enabling HIV transmission, as well as its potential role in driving HIV disease progression, the overlapping global phenomena of HIV and HSV-2 can truly be considered a “syndemic.”
We recommend routine, type-specific serologic test- ing for HSV-2 in all HIV-infected persons. Only tests that detect HSV glycoprotein G are truly type-specific and suitable for HSV-2 serologic screening. Patients with positive results should be informed of the increased risk of transmitting HIV during both symptomatic herpes episodes and phases of asymptomatic viral shedding.
Such patients should be counseled regarding recognition of symptoms of early HSV-2 outbreaks, and may benefit from keeping anti-HSV-2 medications on hand to take when symptoms first develop. Consistent and correct condom use even when HSV symptoms are absent is advisable for maximal protection against transmission of HSV-2 or HIV to uninfected sex partners. Patients with negative HSV-2 serologic results should be counseled about measures to avoid HSV-2 exposure, and their sex partners should be offered serologic testing and counsel- ing regarding chronic suppressive anti–HSV-2 therapy.
Consideration should be given to chronic suppres- sive anti-HSV therapy for HIV- and HSV-2-coinfected patients who experience recurrent symptomatic out- breaks. If a coinfected patient has an HIV-negative, HSV- 2–negative, or dual-negative sex partner, the clinician could also consider chronic HSV-2 suppressive therapy for the patient to decrease the likelihood of HSV-2 and HIV transmission to the uninfected partner. Regimens recommended for chronic suppressive therapy of HSV-2 are acyclovir, 400 mg orally twice daily, or valacyclovir, 500 mg or 1000 mg orally daily (for further discussion, see Chapter 14). At this time, there is no direct clinical evidence to support recommending chronic HSV-2 sup- pressive therapy for HIV-infected patients to slow HIV disease progression; however, clinical trials addressing this question are now being performed.
Gonorrhea, Chlamydia, & Pelvic Inflammatory Disease
According to the CDC’s 2006 STD treatment guide- lines, whether the management of immunodeficient HIV-infected women with pelvic inflammatory disease requires more intensive treatment has not been deter- mined. Such women were more likely to have tubo- ovarian abscesses but responded equally well to standard parenteral and oral antibiotic regimens when compared with HIV-uninfected women.
SEXUALLY TRANSMITTED DISEASES IN HIV-INFECTED PERSONS / 145 Similarly, gonococcal and chlamydial infections do
not seem to cause differing illness or require different treatment in HIV-infected individuals. However, HIV- infected women more often have multiple concomitant reproductive tract infections, a fact that bears remem- bering when assessing and treating such patients.
Bacterial Vaginosis & Trichomoniasis The clinical presentation and recommended treatment of these infections do not differ in HIV-infected patients.
The reader is referred to detailed discussion of these dis- eases elsewhere in this text (see Chapters 11 and 18).
Vulvovaginal Candidiasis
Presentations of candidal vulvovaginitis are generally similar in HIV-infected and uninfected patients but are by definition considered “complicated” when occurring in immunosuppressed patients. Episodes may be more common and more severe among HIV-infected patients and may require longer duration of therapy (7–14 days or more) if standard courses are not effective for indi- vidual patients.
Lymphogranuloma Venereum
This infection is rare in developed countries but more common currently in HIV-infected people than in those without HIV infection. The manifestations and treat- ment of lymphogranuloma venereum are described else- where in this text (see Chapter 17), but the infection bears mentioning here because of its strong epidemio- logic association with HIV-infected MSM, in whom outbreaks in urban areas have recently been reported.
Scabies & Norwegian Scabies
Norwegian (or crusted) scabies, a severe form of scabies that occurs in patients with advanced immunosuppres- sion, is much more common in HIV-infected patients
than in uninfected patients and, like all scabies, is highly contagious. It is best treated with oral ivermectin, 200 mcg/kg as a single dose, followed by a repeat dose 2 weeks later in conjunction with topical permethrin.
Molluscum Contagiosum
This skin and genital condition caused by a poxvirus is much more common in HIV-infected persons and has no apparent long-term adverse effects. It presents as scattered umbilicated papules, usually in the genital area, but can be disseminated in patients with advanced HIV infection.
Treatment consists of ablative cryotherapy, as needed.
PRACTICE POINTS
• The diagnosis of a new STD in a patient with HIV- infection should initiate a broad screening evalu- ation as well as a discussion about sexual risk behavior and the spread of STDs and HIV.
• In the medical care of HIV-infected patients, an increase in HIV viral load or decrease in CD4 T cell count should prompt an evaluation for syphilis infection.
Relevant Web Sites
[Centers for Disease Control and Prevention information on HIV:]
http://www.cdc.gov/std/hiv/default.htm [HIV Medicine Association:]
http://www.HIVMA.org
[National Institutes of Health up-to-date information on HIV:]
htpp://www.niaid.nih.gov/factsheets/hivinf.htm
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