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

       I  HIV/AIDS THEORY

       A. HIV and cytokines

       * BACKGROUND

       Cytokines are chemicals (such as the interferons and
interleukins) that are made by the immune system. The immune system
releases certain cytokines to help recruit cells and manage the
fight against infections. Once the infection is cured other
cytokines are released which help to 'turn off' the response against
the infection.

       * TWO TYPES OF RESPONSES

       There are two types of responses the immune system can make
when it senses an infection. One response is called CMI
(cell-mediated immunity, also known as a type 1 response). Very
simply, CMI involves T cells that fight invading microbes and
destroy infected cells. To boost CMI the immune system makes
cytokines such as:

       - interferon-gamma
       - interleukin-2
       - interleukin-12

       As a general rule, CMI is needed to fight infections caused
by viruses and other microbes that can infect and 'hide' inside
cells.

       The other type of response is called humoral immunity or type
2. Here the immune system relies on antibodies made by B-cells. To
strengthen this response the immune system releases cytokines such
as:

       - interleukin-4 (IL-4)
       - IL-6
       - IL-10

       Interestingly, these cytokines cause cells to make less of
the cytokines needed for CMI. As well, interferon-gamma can cause
cells to decrease production of the cytokines needed for humoral
immunity.

       * HIV

       As a result of new discoveries on the cutting edge of
immunology, researchers have began to form a more sophisticated
model of HIV infection. When the immune system first detects HIV it
can make a response based largely on antibodies or it may try and
contain the infection using T cells. Those people whose immune
systems make the antibodies become "HIV-positive". Despite making
large amounts of antibodies, most patients eventually develop AIDS.
Several research teams have found people who have been exposed to
HIV, yet did not make antibodies. Instead, their immune systems
appeared to contain and manage the infection using T cells. Some
researchers suggest that, over time, those HIV-antibody positive
patients make less of the chemicals that can boost CMI while making
more of the chemicals that help humoral immunity. This shift in
cytokine balance favouring humoral immunity may also be why patients
with HIV/AIDS become allergic to drugs. As CMI weakens, life-
threatening infections appear. Eventually, humoral immunity also
weakens.

       * EARLY WARNING

       Based on results of experiments with cells and HIV, it
appears that HIV-infected immune systems become less able to detect
invading microbes. Moreover, even when T cells are given a
'description' of the microbe(s) they are supposed to attack, their
attempts are weak and the infection is not always contained. In much
of the basic research on HIV it is clear that CD8+ cells are
important in helping fight off many of the infections seen in AIDS.
These cells also play a role in managing the immune system and
should not be thought of as simple 'suppressor' cells. In the next
report we present findings on cytokine therapy.

       ACKNOWLEDGEMENTS:

              1. Thanks to B. Goldberg for helpful discussions,
       access to research papers and researchers.

       REFERENCES:

              1. Mossmann TR, Cherwinski H, Bond MW, et al. Two
       types of murine helper T cell clone: definition according to
       profile of lymphokine activities and secreted proteins.
       Journal of Immunology 1986;136(7):2348-2357.


              2. Mossmann TR. Cytokine patterns during progression
       to AIDS. Science 1994;265:193-194.

              3. Clerici M and Shearer G. The Th1-Th2 hypothesis of
       HIV infection: new insights. Immunology Today
       1994;15(12):575-581.

              4. Rowland-Jones S, Sutton S, Ariyoshi K, et al.
       HIV-specific cytotoxic T cells in HIV-exposed but uninfected
       Gambian women. Nature Medicine 1995;1(1):59-64.

              5. Meyaard B, Otto SA, Keet IPM, et al. Changes in
       cytokine patterns of CD4+ T cell clones in Human
       Immunodeficiency Virus infection. Blood
       1994;84(12):4262-4268.

              6. Maggi E, Giudizi MG, Biagiotti R, et al. Th2-like
       CD8t cells showing B cell helper function and reduced
       cytolytic activity in Human Immunodeficiency Virus type-1
       infection. Journal of Experimental Medicine 1994;180:489-495.

              7. Paganlli R, Scala E, Ansotegui LJ, et al. CD8+ T
       lymphocytes provide helper activity for IgE synthesis in
       Human Immunodeficiency Virus-infected patients with
       hyper-IgE. Journal of Experimental Medicine 1995;181:423-428.

              8. Seder RA and Le Gros GG. The functional role of
       CD8+ T helper type 2 cells. Journal of Experimental Medicine
       1995;181:5-7.

              9. Quill H, Bhandoola A, Trinchieri G, et al.
       Induction of ILr12 responsiveness is impaired in anergic T
       lymphocytes. Journal of Experimental Medicine
       1994;179:1065-1070.

       B. Testing the theory

       * BACKGROUND

       Several research teams have noted a decrease in cell-
mediated (CMI) immunity in EGV-infected patients as their CD4+ cell
counts fall over time. As well, production of cytokines associated
with CMI (interferon-gamma, IL-2 and IL-12) fall in HIV/AIDS while
production of cytokines associated with humoral immunity (IL-4, 6,
10) rise. Thus some researchers are suggesting giving subjects with
HIV/AIDS extra cytokines that may boost CMI. But the immune systems
of such patients are complex and may not necessarily be quickly
repaired when they receive supplements of cytokines.

       * 27 YEARS OF RESEARCH

       One prominent American researcher said that scientists have
been studying cytokines for over 27 years and apart from the bone
marrow stimulants GM-CSF and EPO, cytokine therapy has not been
"terribly successful". This is because cytokines:

       - quickly break down
       - are needed at very small and particular sites
       - can be toxic when taken in large doses

       Some researchers are beginning to suspect that there will not
be any single 'magic' cytokine for treating HIV/AIDS. Leading
immunologists suspect this is the case because there is usually a
'mix' of cytokines that cause certain effects.

       * ANTI-CYTOKINES?

       Some doctors think about using cytokines in a "positive" way;
that is, giving patients extra cytokines such as IL-2 and
interferons. But in lab experiments, adding extra interferon-gamma
did not reduce the effect of IL-4 or IL-10, but using anti-IL-4
antibodies did. In mice infected with a virus that gives them AIDS,
anti-IL-4 antibodies delayed the development of AIDS.

       * TESTING THE THEORY - CANCER

       In the section on cancer in this issue of TreatmentUpdate
researchers found that anti-IL-6 therapy had weak anti-cancer
effects. Their next attempt may include attacking IL-6 and other
cytokines, such as IL-10 with chemotherapy.

       * TESTING THE THEORY - ARTHRITIS

       Researchers in the European Union have used an antibody that
attacked the cytokine TNF-alpha (tumor necrosis factor). Subjects in
that study received a placebo or the anti-cytokine called cA2.
Short-term use of this product improved subjects' quality of life
but did not cure their disease.

       * MAKING A BLOCKADE

       In order for a cytokine to interact with a cell, the cell
usually has a receptor to which the cytokine binds (much like a key
fitting into and opening a lock). Some researchers suggest that
receptor blockers or receptor antagonists should be used to block
the effect of certain cytokines on cells. The problem here is that
when the receptor for the cytokine gets blocked the body continues
to produce high levels of the cytokine. Clearly a more sophisticated
approach needs to be developed.

       Part of the problem is that researchers don't know how to
produce the right mix of cytokines or anti-cytokines that can boost
CMI. Without this information some HIV-infected patients and their
doctors may resort to using products such as:

       - DNCB (TreatmentUpdate 43 and 55)
       - Imreg-1 (TreatmentUpdate 24 and 29)
       - papaverine (TreatmentUpdate 46 and 48)
       - Salk HIV vaccine or Immunogen

that may cause the (delayed-type hypersensitivity) skin reactions
that are the sign of cell-mediated immunity. Preliminary results
from the Salk HIV vaccine trials will appear in a future issue of
TreatmentUpdate.

       REFERENCES:

              1. Barcellini W, Rizzardi GP. Borghi MO, et al. Th1
       and Th2 cytokine production by peripheral blood mononuclear
       cells from HIV-infected patients. AIDS 1994;8(6):757-762.

              2. Bloom B. The power of negative thinking. Journal of
       Clinical Investigation 1993;91:1265-1266.

              3. de Hon FD, Ehlers M, Rose-John S, et al.
       Development of an interleukin (IL) 6 receptor antagonist that
       inhibits IL-6-dependent growth of human myeloma cells. Journal
       of Experimental Medicine 1994;180:2395-2400.

              4. Kanagawa O, Vaupel BA, Gayama S, et al. Resistance
       of mice deficient in IL 4 retrovirus-induced
       Immunodeficiency Syndrome (MAIDS). Science 1993;262:240-242.

              5. Debets R and Savelkoul HFJ. Cytokine antagonists
       and their potential therapeutic use. Immunology Today
       1994;15(10):455458.

              6. Elliot MJ, Maini RN, Feldmann MF, et al.
       Randomized, double-blind comparison of chimeric monoclonal
       antibody to tumour necrosis factor alpha (cA2) versus placebo
       in rheumatoid arthritis. Lancet 1994;344:1105-1110.


       II  IMMUNOMODULATORS

       A. HIV and the kidney

       * BACKGROUND

       In the early 1980s researchers found that some patients with
HIV/AIDS had damaged kidneys. This complication even appeared in
symptom-free patients. In the USA, HIV-infected patients from Miami
and New York were more likely to have kidney dysfunction than
patients from rural areas. In some patients the kidneys remove
protein from the blood and dump it into the urine. Over the long
term, this loss of protein and continued kidney damage may be
dangerous. Researchers in Germany have been studying HIV- related
kidney problems to try and find out why they happen. For their study
the researchers recruited 90 subjects.

       * STUDY DETAILS

       All subjects were adults and had CD4+ cell counts greater
than 500 cells. As well, all subjects received AZT 500 mg/day.
Technicians performed ultrasound and other tests.

       * RESULTS: DRUG USERS AND MEN WHO HAVE SEX WITH MEN

       Looking at ultrasound scans, the researchers could not find
any severe damage to the kidney. About 11 subjects had relatively
high levels of protein in their urine. Gay/bisexual men and
subjects with less than 200 CD4+ cells seemed more likely to have
high levels of protein in their urine. Among the gay/bisexual men
who had high levels of protein loss, 2 had CMV (cytomegalovirus)
infection. When doctors gave these subjects the anti-CMV drug
ganciclovir (DHPG, Cytovene(R)) protein loss dropped dramatically.
Among drug users, high protein loss in the urine happened at CD4+
cell counts above 200 cells. One drug user had high blood levels of
antibodies against the parasite that causes toxo (toxoplasmosis)
Another drug user with a chronic chlamydia infection also had high
levels of protein in his urine.

       In this study the researchers divided the subjects into 4
groups based on how they became infected with HIV; hemophiliacs,
heterosexual/transfusion recipients, gay/bisexual men and injection
drug users. Some gay/bisexual men seemed more likely to have high
levels of protein in their urine. This was still the case when the
researchers looked at the other subjects with similar CD4+ cell
counts. According to the researchers, there may be several reasons
for protein loss and kidney damage:

       - kidney malfunction
       - immune complexes being dumped in the kidney (irnmune
         complexes are a combination of an antibody joined to a
         protein, in this case, to HIV)
       - heroin toxicity
       - other infections

       The researchers warn that patients with high levels of
protein in their urine may be at risk for kidney damage from
acyclovir (Zovirax) and certain antibiotics such as aminoglycosides
(including gentamycin, neomycin and streptomycin).

       REFERENCES:

              1 . Busch HW, Riechrnann ST, Heyen P, et al.
       Albuminuria in HIV- infected patients. AIDS Researeh and
       Human Retrovuuses 1994;10(6):717-720.

       B. Corticosteroids for the kidney?

       * FOUR SUBJECTS

       Doctors in Cleveland, Ohio, have recently reported their
results in treating 4 HIV-infected patients with kidney dysfunction.
All subjects were adults, 2 males and 2 females. Three of these
subjects had used AZT and one, ddI. The CD4+ cell counts ranged from
30 to 80 cells. Doctors treated them with the corticosteroid
Prednisone 60 mg/day "for 2 to 6 weeks." All subjects improved and
protein loss was reduced. The doctors suggested that short-term use
of steroids "does not substantially increase the risk of
life-threatening infections." Two subjects developed MAC infections,
but when the doctors stopped giving the subjects steroids the
patients survived the infection. Other doctors may wish to consider
testing concentrated fish oil (with the vitamins A and D removed) or
flax seed oil (with beta- carotene and vitamin E used as
preservatives) as potential anti-inflammatory kidney treatment.

       REFERENCES:

              1. Smith MC, Pawar R, Carey JT, et al. Effect of
       corticosteriod therapy on human Immunodeficiency
       virus-associated nephropathy. American Journal of Medicine
       1994;97:145-151.

              2. Donadio JV, Bergstralh EJ, Offord KP, et al. A
       controlled trial of fish oil in IgA nephropathy. New England
       Journal of Medicine 1994;331(18):1 194-1 199.

       C. DNCB-long-term results

       * STUDY DETAILS

       For background information on DNCB please see TreatmentUpdate
43. We now report results from a long term observational study on
DNCB. Researchers in California enrolled 24 male, HIV-infected
subjects for this study;

       - 18 subjects "had no symptoms"
       - 6 had persistently swollen lymph nodes
       - the average CD4+ cell count was 346 cells (ranging between
         170 and 560 cells)

       Subjects used a 'Q-tip' to dip into a 10% solution of DNCB
which they then 'painted' on to a "2 inch square of skin" to see if
they had been exposed to DNCB in the past. A month after first
applying the 10% solution subjects began to use a 2% solution on a
2-inch square of their skin. If subjects then had a strong
reaction-redness, itching-they used the weakest strength of DNCB
that could cause a reaction on their skin.

       * STOPPING USE OF THE DRUG

       Eventually researchers found that 13 subjects continued to
use DNCB on a regular basis while another 11 did not. Those subjects
who stopped using DNCB did so after about 11 months. On average,
researchers monitored subjects for over 2 years; some subjects were
observed for almost 4 years. Two subjects also used a combination of
AZT and ddC, two others AZT and ddI and seven others used AZT alone.
Three subjects who used DNCB on a regular basis also took AZT.

       * TOXICITY AND OTHER EFFECTS

       Three subjects had side effects. The first had a rash over
most of his body when he exercised right after his first DNCB patch.
His reaction cleared in two hours. The other 2 subjects had very red
and irritated reactions on the skin where they put a 10% solution of
DNCB. Within 48 hours these reactions cleared. The study's
researchers suggest that DNCB use appears to be "safe" in this small
group of subjects. Three subjects noted that they had "significant"
increases (no precise data provided) in their weight while using
DNCB. According to the researchers, the weight gain did not appear
to be caused by other drugs.

       * SYMPTOMSOF HIV/AIDS

       According to the researchers those subjects who stopped using
DNCB after 11 months "appeared [more likely to develop] AIDS". None
of these subjects stopped using DNCB because they became ill.

       * CD4+CELLS

       Both regular users of DNCB (who had 396 cells at the start of
the study and 211 cells at the end) and non-users (who had 315
cells at the start of the study and 122 cells at the end) had
decreased CD4+ cell counts. This difference between the 2 groups,
with the DNCB users having a less severe decline, was statistically
significant. The different CD4+ counts between the 2 groups at the
start of the trial were not statistically significant.

       * CD8+AND OTHER CELLS

       Subjects who used DNCB on a regular basis had slightly
increased levels of CD8+ (from 1014 to 1093 cells) and NK (natural
killer) cells compared to subjects who did not take the drug on a
regular basis (from 1234 to 920 cells). This difference between the
2 groups was statistically significant. At least 2 studies in the
USA suggest that having a high CD8+cell count may mean that such
subjects are less likely to die than subjects with less than 400
CD8+ cells. Researchers did not carry out any performance tests on
CD8+ and NK cells taken from users of the drug. DNCB also appeared
to increase certain types of CD8+ cells in users, but researchers
are not sure just what this means.

       * INFECTIONS/DEATHS

       Researchers found that 2 of 13 subjects using DNCB on a
regular basis developed skin lesions of KS (Kaposi's sarcoma). In
one subject the lesion faded, in the other no new lesions appeared.
No subject who continued to use the drug died. Five of 11 subjects
who stopped using the drug developed AIDS; 3 had the life-
threatening lung infection PCP; 2 had KS. These 5 subjects used DNCB
for an average of 9 months and developed AIDS about 10 months after
they stopped using the drug. Eventually 4 of the 5 subjects died.
The researchers noted that all the subjects who developed ATDS used
AZT and/or other anti-HIV drugs. This does not necessarily mean that
AZT and related drugs may have been a factor in their deaths. These
subjects may have been sicker at the start of the study and may have
had a higher chance of dying than other subjects. Clearly larger and
controlled studies of DNCB are needed to find out more about this
drug's effects.

       REFERENCES:

              1. Stricker RB, Elswood BF, Goldberg B, et aL CEnical
       and immunologic evaluation of HIV-infected patients treated
       with dinitrochlorobenzene. Journal of the American Academy of
       Dermatology 1994;31(3)part 1:462-466

              2. Giorgi JV, Ho HN, Huji K, et al. CD8+ lymphocyte
       activation of Human Immunodeficiency Virus seroconversion:
       development of HLA-DR+ CD38- CD8+ cells is associated with
       subsequent stable CD4+ levels. Journal of Infectious Diseases
       1994;170:775-781.

       III INFECTION FIGHTERS

       A. Syphilis

       * 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.

       B. Azithromycin for syphilis?

       * 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.

       C. Syphilis in the brain

       * 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.

       IV CANCER

       A. Cytokines and cancer

       * BACKGROUND

       Researchers in the EU and USA have noted that some patients
with certain cancers have T cells that do not function properly. In
one study of cancer (Hodgkins disease using non-HIV-infected
subjects) researchers found that subjects with the weakest T cell
response usually had the most severe complications of cancer. In
such patients, cell-mediated immunity was poor. These researchers
have also documented a similar trend in patients with HIV/AIDS.
According to the researchers' theory, as the immune system breaks
down, more chemicals are released that weaken CMI. Such chemicals
include the cytokines:

       - 4 (interleukin 4)
       - IL-6
       - IL-10

       These chemicals reduce the production of IL-2 and
interferon-garnma and favour the growth of more B cells. Perhaps
under this chemical stimulation and infection with herpes viruses it
is not surprising that B cell cancers occur in AIDS. Treatment of
these cancers consists of a combination of anti-cancer drugs-
chemotherapy. These drugs are not always effective. Some researchers
in France think that by giving patients with AIDS-related cancer
anti-cytokines, their quality of life and perhaps survival may be
improved, compared with similar patients not given these drugs.

       REFERENCES:

              1. Clerici M and Shearer G. The Thl-Th2 hypothesis of
       HIV infection: new insights. Immunology Today
       1994;15(12):575- 581.

              2. Benjamin D, Knobloch TJ and Dayton MA. Human B-cell
       interleukin-10: B-cell lines derived from patients with
       Acquired Immunodeficiency Syndrome and Burkitt's lmphoma
       constitutively secrete large quantities of IL-10. Blood
       1992;80(5):1289.

       B. Lymphoma: BE-8 may improve quality of life

       * BACKGROUND

       Researchers in France have created an antibody that attacks
the cytokine IL-6 (interleukin 6). Their antibody, called BE-8, was
originally made by cells from mice. This antibody had been tested on
non-HIV-infected patients with cancer and did not appear to cause
any serious toxicity. Our report provides results from a study
called ANRS 018.

       * TYPE OF SUBJECTS

       Researchers enrolled 11 HIV-infected subjects (9 males, 2
females) with B cell lymphoma in this study. All subjects had less
than 40 CD4+cells when they entered the study. Researchers did not
release the subjects' CD8+ cell counts. Before entering the study
five subjects had received chemotherapy but despite treatment their
tumours grew. While receiving infusions of BE-8 subjects did not
receive chemotherapy or radiation one month before or during this
study. Subjects had tumours in a variety of places including the
lung, face, stomach and testicles.

       * DRUGS AND MONITORING

       Researchers gave the subjects 125 ml of salt solution which
contained BE-8. Technicians took blood samples from subjects to
measure a protein called CRP (c-reactive protein). Production of CRP
in the liver falls when IL-6 levels decline. As well, doctors also
compared the size of tumours before and after subjects received
BE-8. At first "3 [subjects received] 10 mg/ day of BE-8." Since CRP
levels were still high, the dose of BE-8 was increased to 20 mg/day
and up to 40 mg/day if CRP levels did not fall. Subjects were
supposed to receive the drug for at least 3 weeks or 1 cycle. Some
subjects received the drug for longer periods of time.

       * RESULTS

       During the first 21 days of the study about 1/2 the subjects
stabilized. Only 4 subjects received BE-8 for more than 21 days. The
drug caused CRP levels in the blood to fall and also delayed the
growth of the cancer for between 57 and 91 days.

       * SYMPTOMS

       Doctors found that 4 subjects with symptoms of lyrnphoma
(such as fever and night sweats) had some relief when they received
BE-8. Other subjects had increased appetite and weight. Those
subjects who received more than 1 cycle of BE-8 continued to gain
weight.

       * SIDE EFFECTS

       Subjects did not report many side-effects. One subject had
headaches "1 hour after" receiving BE-8. No subject had
life-threatening infections while in the study. Researchers did
allow subjects to use anti-PCP/toxo drugs. All subjects had less
than normal levels of platelets (needed for clotting blood) but they
did not suffer from prolonged bleeding. Blood levels of white cells
called neutrophils fell in subjects but this did not cause any
complications. Two subjects rnade antibodies that attacked BE-8 but
this did not appear to cause increased growth of the tumours.

       * SUMMARY

       While infusions of anti-IL-6 appeared to stop the growth of
tumours in some subjects, eventually the tumours continued to grow.
BE-8 did affect symptoms of Iymphoma clearing "fever, sweats and
[weight loss]". The French research team suggested that combination
treatment of AIDS-related Iymphoma with BE-8 and anti-cancer drugs
should be tested to see if survival is lengthened. BE-8 may also
provide some relief from symptoms for other subjects with cancer.

       * CYTOKINES AND CANCER

       Clearly, anti-IL-6 had only weak anti-cancer effects. While
researchers have documented changes in the type of cytokines
released in patients with HIV/AIDS, trying to use just one type of
anti-cytokine is not enough. Effective treatment may require a more
sophisticated approach, perhaps blocking the effects of other
cytokines such as IL-4 and IL-10. The monoclonal antibody used in
this study was made and purified by technicians associated with this
trial.

       REFERENCES:

              1. Clerici M, Ferrario E, Trabattoni D, et al.
       Multiple defects of T helper cell function in newly diagnosed
       patients with Hodgkins disease. European Journal of Cancer
       1994;30A(10):1464-1470.

              2. de Hon FD, Ehlers M, Rose-John S, et al.
       Development of an interleukin (IL) 6 receptor antagonist that
       inhibits the growth of human myeloma cells. Journal of
       Experimental Medicine 1994; 180:2395-2400.

              3. Emille D, Wijdenes J, Gisselbrecht C, et al.
       Administration of an anti-interleukin-6 monoclonal antibody
       to patients with Acquired Immunodeficiency Syndrome and
       Iymphoma: effect on Iymphoma growth and on B clinical
       symptoms. Blood 1994;84(8):2472-2479.

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