                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                          March 8, 1996

                Opportunistic Infections (Part XXI)
                     Syphilis/Neurosyphilis

[Oportunistic Infections and Related Disorders; From AmFAR's
AIDS/HIV Treatment Directory, Vol. 7, No. 3, January 1995]

     PATHOGEN: Treponema pallidum, a spirochetal bacterium.

     SITES OF INFECTION: Soon after initial infection, the organism
enters the lymphatic system and/or blood stream and disseminates
throughout the body. Nearly all organs can be invaded, including
the central nervous system.

     SYMPTOMS: Primary syphilis is characterized by a chancre (a
sore or lesion) at the site of inoculation. This chancre does not
always develop, however, and multiple chancres are also possible.
Lymphadenopathy accompanies the chancre. Symptoms of secondary
syphilis can include rash, condyloma lata, lymphadenopathy, various
constitutional symptoms, and less frequently, others, including
meningitis. It should be noted that neurosyphilis can occur at any
stage of syphilis; syphilitic meningitis and meningovascular
syphilis occur early (months to a few years after infection) and
general paresis and tabes dorsalis occur later (5-30 years after
infection). In addition to neurosyphilis, late syphilis can affect
almost any organ through gummatous lesions and cardiovascular
involvement. Johns et al. hypothesize that co-incident HIV
infection accelerates the course of syphilis, and Flood et al.
report that symptomatic early neurosyphilis may be more common in
HIV-infected people.

     DIAGNOSIS: In early syphilis, darkfield examination of exudate
from lesions and direct florescent antibody tests on lesions or
tissue are definitive. Serological tests include non-specific,
non-treponemal assays and specific treponemal assays. Non-specific
tests are useful for syphilis screening and for monitoring response
to treatment. Specific tests are used for definitively establishing
a diagnosis. They usually remain positive for life and therefore
cannot be used to monitor response to treatment. CSF examination
is necessary for diagnosis of neurosyphilis.
     In HIV-infected individuals, false-positive serological tests
despite adequate therapy are possible due to polyclonal B-cell
activation or auto-immune processes. Conversely, but extremely
rarely, false-negative serological tests have been reported.
Extraordinary means (such as direct examination of lesion material)
may be necessary to establish the diagnosis in these unusual cases.

     TREATMENT RESULTS: Standard treatment for early syphilis is
parenteral penicillin (benzathine penicillin G). However,
prospective studies to establish the most effective drugs and
dosages have not been conducted. CDC recommends a single dose of
2.4 million units of benzathine penicillin G administered
intramuscularly for both HIV-negative and HIV-infected patients.
Musher et al. propose higher doses (three 2.4 million unit doses
at weekly intervals) in order to prevent possible relapse to
neurosyphilis. While ceftriaxone (500 mg or 1 g IM qd for 10 days)
may be an effective alternative regimen, it has not been
conclusively evaluated. In the penicillin-allergic HIV+ patient
with early syphilis, some clinicians use doxycycline as an
alternative to desensitization or ceftriaxone.
     For late latent syphilis of more than one year's duration with
no CSF evidence of neurosyphilis, CDC guidelines recommend 7.2
million units of benzathine penicillin given in three weekly doses
IM.
     CDC guidelines for neurosyphilis recommend aqueous crystalline
penicillin G 2 to 4 million units IV every four hours for 10 to 14
days (total dose 12 - 24 million units). Alternative regimens
include procaine penicillin 2 to 4 million units IM daily plus
probenecid 500 mg IM four times daily for 10 to 14 days.
     A study of 11 HIV+ patients with syptomatic neurosyphilis
receiving aqueous crystalline penicillin G potassium (18-24 million
units daily for 10 days) concluded that HIV infection may affect
both the natural course of syphilis and the response to treatment
(Gordon et al.). At 24 weeks after treatment, serum titers on rapid
plasma reagin (RPR) of four patients decreased by at least two
doubling dilutions, and four patients had reductions in the
cerebrospinal fluid titers. In two patients, there was no
normalization or improvement in serum titers, and one patient
relapsed with meningovascular syphilis six months after therapy.
     Gourevitch et al. conducted a cohort study of 50 intravenous
drug users with syphilis. 31/50 were HIV-positive and 19/50 were 
HIV-negative. HIV infection did not alter the response to
treatment. Most patients had late latent syphilis at presentation
(15/31 and 13/19 patients in the HIV-positive and HIV-negative
groups, respectively). Follow-up was adequate to assess treatment
outcomes in 43 patients (26 HIV-positive and 17 HIV-negative). A
variety of treatment regimens were used. Among the evaluable
HIV-positive patients, 12 received the standard CDC-recommended
regimen of penicillin and 14 received other therapy (either high
doses of penicillin or non-penicillin regimens). All responded
adequately to therapy. Among the HIV-negative subjects, 9 received
standard therapy and 8 received other therapy. One patient (who
received two weeks of tetracycline) did not respond adequately.
     Dowell et al. retrospectively compared ceftriaxone (1-2 g/day
for 10-14 days) and benzathine penicillin (2.4 million units weekly
for three weeks) for late latent syphilis or asymptomatic
neurosyphilis in HIV-infected patients. 28/44 ceftriaxone
recipients and 8/13 benzathine-penicillin recipients responded to
treatment. The investigators concluded that ceftriaxone and
benzathine penicillin appear equivalent for patients with normal
CSF.

     Trials are underway comparing IV ceftriaxone and IV penicillin
G for neurosyphilis, and alternate penicillin regimens for
syphilis.

REFERENCES: Centers for Disease Control and Prevention. Sexually
Transmitted Disease Treatment Guidelines. Syphilis. Morbidity and
Mortality Weekly Report. 1993;42(suppl RR-14):27-46).

     Dowell ME et al. Response of latent syphilis or neurosyphilis
to ceftriaxone therapy in persons infected with human
immunodeficiency virus. Amer J Med 93:481-8, 1992.

     Flood JM et al. Neurosyphilis in San Francisco during the AIDS
epidemic, 1985-1989. 31st ICAAC, abstract 334, 1991.

     Gordon SM et al. The response of symptomatic neurosyphilis to
high-dose intravenous penicillin G in patients with human
immunodeficiency virus infection. NEJM 331:1469-1473, 1994.

     Gourevitch MN et al. Effects of HIV infection on the serologic
manifestations and response to treatment of syphilis in intravenous
drug users. Ann Int Med 118:350-5, 1993.

     Johns DR et al. Alteration in the natural history of
neurosyphilis by concurrent infection with the human
immunodeficiency virus. NEJM 316:1569-72, 1987.

     Musher DM et al. Effect of HIV infection on the course of
syphilis and on the response to treatment. Ann Int Med 113:
872-881, 1990.

OTHER REPORTS: Hook EW and Marr CM. Acquired syphilis in adults
(review). NEJM 326: 1060-9, 1992.

     Johnson PDR et al. Specific syphilis serological tests may
become negative in HIV infection. AIDS 5: 419-23, 1991.

     Matlow AG et al. Syphilis serology in HIV-infected patients
with symptomatic neurosyphilis: case report and review. Rev Infect
Dis 12:703-7, 1990.

     Musher DM et al. Neurosyphilis in HIV-infected persons. NEJM
331:1516-1517, 1994.

     Pope V et al. Effect of syphilis and HIV coinfection on
expression of peripheral blood lymphocyte immunophenotypes.
Abstract #L8, 34th ICAC, Orlando, 1994.

     Copyright (c) 1995 - American Foundation for AIDS Research
(AmFAR) - All Rights Reserved. Permission to reproduce for
non-profit use granted with the condition that the source and date
of the information  be given, and that AmFAR be notified. Eric
Fretz, Treatment Information Services, AmFAR. DISTRIBUTED BY
GENA/aegis (714.248.2836 * 8N1/Full Duplex * v.34).

                  INFECTION FIGHTERS: Syphilis
                         by Sein Hosein

[Treatment Update 55 - Vol. 7, No. 1 - January 1995; Published by
Community AIDS Treatment Information Exchange, Suite 420-517
College Street, Toronto, Ontario, Canada M6G 4A2.]

* BACKGROUND

     Infections normally kept under control may reappear as the
immune system begins to break down under constant attack by HIV.
A number of researchers have claimed that in patients with
HIV/AIDS:

     - lab tests for syphilis may not be accurate
     - standard anti-syphilis therapy may not be effective
     - chronic infection with T. pallidum (the cause of syphilis)
     may weaken the immune system

     Doctors at a clinic in Baltimore, Maryland, have been studying
the interaction between syphilis and HIV. By reviewing records on
over 300 patients (both HIV- infected and non-infected) from their
clinic they hoped to find information that might be useful when
caring for HIV-infected patients who also have syphilis.

* STUDY DETAILS

     The doctors looked at data from patients with primary or
secondary syphilis or early latent syphilis. Patients who had
primary syphilis had:

     - an ulcer on their genitals
     - detectable T. pallidum in samples from those ulcers
     - a 'positive' FTA-ABS test (reactive fluorescent treponemal
     antibody absorption test). Researchers used this test because
     it gave them more accurate results than the RPR (rapid plasma
     reagin test card) test.

     Patients with secondary syphilis had:

     - rash
     - mucous patches
     - wart-like lesions, and a 'positive' RPR/FTA-ABS test in the
     past 12 months. Prior to this their test result was
     'negative'.

     Patients with early syphilis had:

     - no symptoms
     - had a 'positive' RPR/FTA-ABS while in the past 12 months
     these tests had been 'negative'.

* RESULTS

     The researchers found that HIV+ patients (both men and women)
were more likely to have secondary syphilis than early syphilis.
There was a trend when the researchers looked at CD4+ cell counts.
Subjects with less than 500 CD4+ cells were more likely to have
secondary syphilis. All four patients with less than 200 CD4+cells
had secondary syphilis.

* TREATMENT

     Patients received either one injection of benzathine
penicillin or 200 mg/day of doxycycline for 2 weeks. Despite this
treatment 16 subjects did not recover. Interestingly, fifteen of
these patients had received the single injection of benzathine
penicillin. Eighteen percent of HIV-infected and 14% of the
non-HIV-infected did not respond properly when they received
treatment. This difference was not statistically significant.

REFERENCES:

     1. Hutchinson CM, Hook EW, Shepard M, et al. Altered clinical
presentation of early syphilis in patients with Human
Immunodeficiency Virus infection. Annals of Internal Medicine
1994;121 :94-99.

     Copyright (c) 1995 - TreatmentUpdate.  Distributed by AEGIS,
714.248.2836 * 8N1/Full Duplex * v.34

         INFECTION FIGHTERS: Azithromycin for Syphilis?
                         by Sein Hosein

[Treatment Update 55 - Vol. 7, No. 1 - January 1995; Published by
Community AIDS Treatment Information Exchange, Suite 420-517
College Street, Toronto, Ontario, Canada M6G 4A2]

* BACKGROUND

     For treating patients with syphilis, the CDC (Centers for
Disease Control and Prevention, Atlanta, Georgia) recommends using
the antibiotic penicillin. Penicillin may not work in some patients
and others may be allergic to it. Alternatives include ceftriaxone,
tetracyclines and erythromycin. The CDC recommends that
erythromycin should only be used for early treatment of syphilis
where the patient can be monitored for 12 months. Azithromycin is
an antibiotic that is 'related' to erythromycin and clarithromycin
which some doctors use to treat patients with MAC and 'toxo'
(toxoplasmosis). The company that sells azithromycin, Pfizer, has
been studying the effect of azithromycin on subjects with primary
and secondary syphilis. In previous work azithromycin can block the
growth of T. pallidum (the cause of syphilis) and is effective in
treating rabbits with syphilis.

* STUDY DETAILS

     All 16 subjects were adults (10 male and 6 female) and the
doctors recruited them from a clinic that specialized in the
treatment of sexually transmitted diseases. Subjects were supposed
to take 500 mg/day of azithromycin "for 10 days." Over the next 6
months most subjects returned to the clinic for observation and lab
tests. Three subjects did not return for follow-up visits.

* RESULTS

     According to the researchers, 11 subjects were "cured". The
doctors based their diagnosis on the results of blood tests. As 
well, subjects who recovered usually had their symptoms (such as
sores on their genitals, swollen lymph nodes and rash) clear. Two
other subjects were not cured; either they never recovered or were
re-infected.

* TOXICITY

     Five subjects had some side effects including nausea,
vomiting, "mild cramps, loose stools or diarrhea." Subjects
described these symptoms as "mild" except for the one subject who
vomited. No toxicity to the bone marrow, liver or kidney was
detected.

* HIV

It is not clear what will happen to other patients with both HIV
and syphilis who are treated with azithromycin. Some researchers
note that there is a complex interplay between T. pallidum and the
irnmune system. As well, diagnostic technology for syphilis
generally seems not to have advanced the way tests for some other
diseases have. Perhaps better tests may make clear what happens
when HIV+ patients become infected with T. pallidum.

REFERENCES:

     1. Verdon MS, Handsfield HH and Johnson RB. Pilot study of
azithromycin for primary and secondary syphilis. Journal of
Infectious Diseases 1994;19:486-488.

     2. Fitzgerald TJ. The Th1/Th2-like switch in syphilitic
infection: is it detrimental? Infection and Immunity 1992;60(9):
3475- 3479.

     3. Riley BS, Oppenheier-Marks, Rodolf JD and Norgard MU.
Virulent treponema pallidum promotes adhesion of leucocytes to
human vascular endothelial cells. Infection and Immunity
1994;62(10):4621-4625.

     Copyright (c) 1995 - Treatment Update.  Distributed by AEGIS,
714.248.2836 * 8N1/Full Duplex * v.34

            INFECTION FIGHTERS: Syphilis in the Brain
                         by Sein Hosein

[Treatment Update 55 - Vol. 7, No. 1 - January 1995; Published by
Community AIDS Treatment Information Exchange, Suite 420-517
College Street, Toronto, Ontario, Canada M6G 4A2]

* SYMPTOMS

     Researchers in Atlanta studied the effect of standard
treatment for neurosyphilis in 11 HIV-infected subjects (9 male,
2 female). The subjects were all adults and tested 'positive' for
syphilis on standard tests (listed in section A). Medical staff
performed a spinal tap to get a sample of CSF (cerebrospinal spinal
fluid; in which the brain and spinal cord float). Technicians
tested the CSF samples for the microbe that causes syphilis as well
as antibodies that suggest syphilis. Subjects had the following
signs/symptorns of neurosyphilis:

     - eye inflammation
     - swollen/damaged retina
     - stroke
     - life-threatening brain infection
     - "behavioural changes" (the researchers did not provide
     details about this symptom)

     Some subjects also had other symptoms-rashes on the hands and
feet. Three subjects also had lost hair on parts of their bodies.
About half the subjects had a CD4+ cell count of 344 cells. Doctors
gave subjects intravenous penicillin G, 18 million to 24 million
units daily for 10 days.

* REACTIONS TO TREATMENT

     Six weeks after receiving treatment technicians analysed blood
and CSF samples. Using one test called VDRL, it appeared that 7 of
11 subjects recovered from their infection. In 2 of the 4 remaining
subjects, it appeared that the infection was not getting worse
while in 2 others the infection seemed to get worse. The doctors
suggested that the immune systems of these 4 subjects could not
contain the infection.

* SIX MONTHS LATER

     Eventually, it appeared that 4 subjects recovered. In 6
subjects analysis of CSF sarnples revealed high levels of white
blood cells-suggesting continued infection. Three of these subjects
who received additional treatment continued to have high levels of
white blood cells in their CSF. Overall, 10 of the 11 subjects had
their signs/symptoms of neurosyphilis clear. One subject had
symptoms of neurosyphilis (including blindness) that became worse
despite aggressive treatment (24 million units/day of penicillin
for 2 weeks). By the sixth month she developed more symptoms such 
as headaches and she had difficulty controlling muscles on the
right side of her body. Doctors gave her another 2 week course of
"high-dose" penicillin but she "died 2 months later."

* WHAT TO DO?

     High levels of white blood cells in the CSF samples from these
HIV-infected subjects suggested that T. pallidum infection
continued. Doctors are not sure what to do for such patients. Some
doctors wait several months to see if the level of white blood
cells in the CSF falls. It may take between 6 and 12 months for
this to happen. Using PCR (polymerase chain reaction), technicians
found T. pallidum in only 3 of 11 subjects before they received
antibiotic therapy. But this probably means that PCR is not
"sensitive" enough because all subjects had signs/symptoms of    
neurosyphilis. Despite increasing the dose of penicillin, T.     
pallidum infection seemed to get out of control suggesting that
this microbe is resistant to penicillin. It is not always clear
which patients will recover. Indeed, 3 of the subjects in this
trial whose infection became worse did not have the "lowest" CD4+
cell counts. The doctors in this study state that other anti-
syphilis therapies need to be tested. 
     As well, because of the difficulty in predicting who will
recover from neurosyphilis, the doctors also state that patients
with neurosyphilis need "intensive evaluation...including CSF
examination, and very careful follow up."

REFERENCES:

     1. Gordon SM, Eaton ME, George R, et al. The response of
symptomatic neurosyphilis to higidose intravenous penicillin G in
patients with Human Immunodeficiency Virus infection. New England
Journal of Medicine 1994;331(22):1469-1473.

     Copyright (c) 1995 - Treatment Update.  Distributed by AEGIS,
714.248.2836 * 8N1/Full Duplex * v.34


                          Editor's Note

     In addition to the guidelines published by CDC (Centers for
Disease Control and Prevention. Sexually Transmitted Disease
Treatment Guidelines. Syphilis. Morbidity and Mortality Weekly
Report. 1993;42(suppl RR-14):27-46), see also Clinical Practice
Guidelines: Testing and Treatment of Syphilis. Journal of the
Physicians Association for AIDS Care. 1994 March;1(3):13-19.
