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 common. HIV-infected patients are more
likely to have chancres of primary syphilis at the same time as
they manifest symptoms of secondary syphilis. In addition, more
protracted 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
involvement at all stages of syphilis infection. Neurosyphilis presentations
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 testing results in HIV-infected
patients may be different in seemingly paradoxical ways (see Table
21–5). For example, HIV-infected patients in the early
stages of HIV disease 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 suspicion 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.
Table 21–5. Results of Serologic Syphilis Testing in Early- and Late-Stage HIV Infection. ||Download (.pdf)
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 (RPR, VDRL)||Higher titers in patients with syphilis||Occasional false-negative results in patients with syphilis|
|Occasional false-positive results in patients without syphilis|
|Nontreponemal titers post-treatment||Higher rate of serologically defined treatment failures may be misleading due to slower decline of titers in patients who had meaningful clinical response||More frequent loss of prior reactivity|
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 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
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
nervous system involvement. A serum RPR titer of 1:32 or higher
combined with a peripheral blood CD4 cell count of 350 cells/μL
or lower conferred still higher odds of neurosyphilis in HIV-infected
patients. Thus, a possible strategy 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]/μL)
can be attributed to HIV infection alone, especially when CD4 counts
are higher than 500 cells/μL, most experts
would consider more than 20 WBCs/μL 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/μL), the significance 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 neurosyphilis who have falsely negative
CSF VDRL results, as well as in many patients without other evidence
of neurosyphilis. 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 equivocal 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 recommended 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 following 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/μL.
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 cervical 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 neoplasm, 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 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 mechanism
of enhanced HIV transmission between an asymptomatic 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 present, determinants of HSV-2 asymptomatic viral
shedding 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, numerous, painful, prolonged, or atypical.
In fact, chronic HSV-2 ulcers of more than 1 month’s duration
are considered an AIDS-defining illness in HIV-infected individuals.
HSV-2 ulcers appear frequently in the perianal area of HIV-infected
people. In severely immunocompromised patients, HSV-2 may present
as hyperkeratotic 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 complications of HSV-2 infection are rare, occur mostly
in advanced AIDS, and develop rapidly. These complications can include
aseptic meningitis, sacral radiculopathy, 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
Among HIV- and HSV-2–coinfected patients treated with
high-dose acyclovir therapy to suppress HSV reactivation, 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 replication 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 testing 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 counseling regarding chronic suppressive
Consideration should be given to chronic suppressive anti-HSV
therapy for HIV- and HSV-2-coinfected patients who experience recurrent
symptomatic outbreaks. 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 suppressive 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 guidelines,
whether the management of immunodeficient HIV-infected women with
pelvic inflammatory disease requires more intensive treatment has
not been determined. 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.
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 remembering
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 diseases elsewhere in this text
(see Chapters 11 and 18).
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 individual patients.
This infection is rare in developed countries but more common
currently in HIV-infected people than in those without HIV infection.
The manifestations and treatment of lymphogranuloma venereum are
described elsewhere in this text (see Chapter 17), but the infection
bears mentioning here because of its strong epidemiologic association
with HIV-infected MSM, in whom outbreaks in urban areas have recently
Scabies & Norwegian Scabies
Norwegian (or crusted) scabies, a severe form of scabies that
occurs in patients with advanced immunosuppression, 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.
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.