       TreatmentUpdate59 - Vol 7, No. 5 (May 1995)
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       Community AIDS Treatment Information Exchange
       Suite 420 - 517 College Street, Toronto M6G 4A2
       (416) 944-1916.
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       Table of Contents

       I   IMMUNOMODULATORS
           A. Thalidomide for ulcers
           B. Low-dose corticosteroids for MAC?

      II   INFECTION FIGHTERS
           A. Preventing PCP---Bactrim/Septra 3 days a week
           B. Toxo---standard treatment
           C. Treating toxo with clarithromycin and minocycline
           D. Roxithromycin---preventing TB/MAC and toxo?
           E. Predicting who will get toxo

     III   TOXICITY
           A. Warning about thalidomide
           B. Reducing the toxicity of sulpha drugs
           C. Experiments in France

      IV   TESTING
           A. Skin tests to predict infections
           B. Skin tests on HIV-infected and non-infected people.
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       I IMMUNOMODULATORS

       A. Thalidomide for ulcers

       * BACKGROUND

       Some patients with HIV infection develop painful sores and
ulcers on the skin, in the mouth and throat, intestines and other
parts of the body. In some cases these ulcers may be caused by
viruses such as CMV (cytomegalovirus) and HSV (herpes simplex
virus). Bacteria and fungi can also cause ulcers. In cases where
technicians have found microbes causing the ulcer, treatment with
drugs-antibiotics, antifungals or antivirals-can bring some relief.
There are cases where the ulcers do not appear to be caused by
microbes. In such cases the ulcers may be caused by the immune
system attacking parts of the body. Drugs that can 'suppress' the
activity of the immune system may provide benefit. Corticosteroids
may be helpful and doctors in Australia have recently reported their
experience with the tranquilizer thalidomide.

       * STUDY DETAILS

       Researchers reviewed hospital records on 20 HIV-infected
subjects who had ulcers and who received thalidomide. All of these
doctors had prescribed a variety of drugs for treating ulcers on
their patients but none worked. All subjects were adult males and
most (80%) had less than 200 CD4+ cells. Subjects received
thalidomide 200 mg/day for 2 weeks taken at night. In some cases
doctors increased the dose of thalidomide to 300 mg/day and in
others the dose remained the same but they received thalidomide
for 2 months.

       * RESULTS

       In 70% of cases the ulcers healed; in others, they became
smaller and less painful. Subjects with ulcers in their rectum
required prolonged treatment-more than 2 weeks. About 1/3 of
subjects developed side effects:

        rash-5 subjects
        nerve damage (peripheral neuropathy)--1 subject
        "excessive [tiredness, low energy]"--1 subject

       The rash cleared when subjects stopped taking the drug.
Others continued using thalidomide despite rash. The nerve damage
cleared when the affected subject stopped using thalidomide. About
1% of non-HIV-infected subjects given thalidomide may develop a
rash. The subject who felt 'excessive [tiredness and low energy]'
stopped using thalidomide (the doctors did not state how long it
took him to recover). Giving subjects the drug at night or reducing
the dose to 100 mg/day seemed to reduce drowsiness during the day.

       * THALIDOMIDE AND THE IMMUNE SYSTEM

       The doctors conducting the study noted that thalidomide did
not reduce CD4+ cell counts. Examination of their data revealed that
9 subjects had decreased CD4+ cell counts while 5 had increased CD4+
cell counts. Unfortunately CD4+ cell counts alone do not reveal the
complex state the immune system is in when infected with HIV.
Information on the effect of thalidomide on the immune system
appears in the section on toxicity later in this issue of
TreatmentUpdate.

       REFERENCES:

              1. Paterson DL, Georghiou P, Allworth AM and Kemp R.
       Thalidomide as treatment of refractory aphthous ulceration
       related to Human Immunodeficiency Virus infection. Clinical
       Infectious Diseases 1995;20:250-254.

       B. Low-dose steroids for MAC?

       * BACKGROUND

       Infection with MAC (Mycobacterium avium complex) can be a
problem for some HIV-infected patients who have less than 75 CD4+
cells. Symptoms can include:

        fever
        unintentional weight loss
        night sweats
        tiredness/low energy
        diarrhea

       As well, some patients might have high blood levels of liver
enzymes such as alkaline phosphatase. Researchers in North America
are conducting clinical trials of drugs that may be used to treat
patients including:

        azithromycin
        clarithromycin
        rifabutin

       Some researchers think that low doses of corticosteroids (1
to 4 mg/day) such as dexamethasone may be useful in relieving some
of the symptoms of MAC infection.

       * STUDY DETAILS

       All subjects had less than 11 CD4+ cells, unintentional
weight loss and fever despite treatment with a combination of 3
antibiotics, one of which was clarithromycin. Technicians detected
high blood levels of a liver enzyme (alkaline phosphatase) and low
blood levels of protein in the blood samples of subjects. They
received 1 to 4 mg/day of dexamethasone orally.

       * RESULTS

       Subjects had an average weight increase of 31 pounds which
lasted for an average of 5 months. Fever decreased as did liver
enzyme levels. Blood levels of protein increased. Four subjects
received therapy for an average of 9 months, until they died.

       * TOXICITY

       Doctors stopped giving one subject steroids because he
developed the sight-threatening infection CMV retinitis. The drug
may also have caused oral yeast infections and possible damage to
the pancreas gland in 2 subjects, one of whom developed high blood
levels of sugar. Four of these subjects died-perhaps because of
several infections that may have been made worse by the
corticosteroid. That one subject developed CMV retinitis is not
surprising. Doctors in England reported that HIV-infected subjects
who used high doses of corticosteroids seemed more likely to develop
CMV retinitis. (For details please see TreatmentUpdate 42). The
doctors treating this group of 4 subjects suggested that subjects
who are using the antibiotics rifampin and 'related' drugs
(rifabutin, rifamycin) may need higher doses of corticosteroids.

       REFERENCES:

              1. Wormser GP, Horowitz H and Dworkin B. Low-dose
       dexamethasone as adjunctive therapy for disseminated
       Mycobacterium avium complex infections in AIDS patients.
       Antimicrobial Agents and Chemotherapy 1994;38(9):2215-2217.

       II  INFECTION FIGHTERS

       A. Preventing PCP-Bactrim/Septra 3 days weekly

       * BACKGROUND

       Although guidelines by the US Public Health Service suggest
that HIV-infected patients should receive preventative doses of
Bactrim(R)/Septra(R) every day, some doctors disagree with this
schedule. (Bactrim/Septra (B/S) are the brand names of a combination
of 2 antibiotics. The regular dose [also called single strength] has
80 mg trimethoprim and 400 mg sulphamethoxazole. The double strength
(DS) has 160 mg trimethoprim and 800 mg sulphamethoxazole.) A few
studies suggest that using B/S 3 times per week may be as effective
as daily use in preventing PCP. Intermittent doses of B/S may be
less toxic for patients and may delay the growth of microbes which
are resistant to that drug.

       Researchers in California have been conducting experiments on
HIV-infected subjects with B/S and AZT. Preliminary results from
their work suggest that B/S three times weekly is easier to tolerate
than daily doses.

       * STUDY DETAILS

       Researchers used data from 107 HIV-infected subjects who
entered the study with less than 200 CD4+ cells (the average CD4+
cell count was about 140 cells). Subjects who had severe and
life-threatening reactions to sulpha drugs were not allowed to enter
this study. Subjects randomly received either B/S single strength
twice daily or the same dose taken on Monday/ Wednesday/Friday. Some
subjects also received 10 mg/day leucovorin, an artificial form of
the B-vitamin folic acid, to protect their bone marrow from the side
effects of AZT and B/S. Initially subjects received 1 g/day of AZT
which was later reduced to 500 mg/day. Researchers did not release
details on the sex of subjects.

       * RESULTS

       Forty-two percent (42%) of 52 subjects receiving daily B/S
had to stop taking that drug because of bone marrow toxicity. For
subjects taking B/S thrice weekly 24% had to stop for the same
reason. Using leucovorin did not seem to have any effect in reducing
bone marrow toxicity or influencing which group of subjects left the
study. However, researchers noted that subjects who received
leucovorin were 6 times less likely to develop bone marrow toxicity
than subjects not taking that drug. This difference was not
statistically significant. Subjects taking B/S thrice weekly were
more likely to keep taking the drug (68%) than subjects taking the
daily dose (51%). This difference between the two arms of the study
was statistically significant; that is, not likely due to chance
alone.

       * TOXICITY

       The most common side effect was "headache". Problems with
intestinal toxicity were reported, with "nausea" being the most
common. Fatigue was also another side effect in a small number of
subjects.  Interestingly, serious bone marrow damage did not occur.
A small number of subjects stopped using B/S because they developed
several side effects including 'neurological complaints (the doctors
did not provide further details), fever and fatigue'. The
researchers checked a number of factors (including high doses of AZT
versus low; AIDS versus ARC) but these did not help them predict
which subjects would develop drug toxicity.

       * WHY WAS THERE A DIFFERENCE?

       The researchers are not sure why subjects receiving thrice
weekly B/S were better able to tolerate the drug than those taking
it every day. No subject receiving B/S developed PCP. One subject
developed the life-threatening brain infection 'crytpo'
(Cryptococcus neoformans) and another a bacterial infection. No
subject developed infections such as toxo or MAC which can be
affected by B/S. As subjects taking B/S three times weekly were much
more likely to continue taking their drug than those who received it
daily, this may have an impact on who develops infections such as
PCP/toxo over the long term.

       REFERENCES:

              1. Bozzette SA, Forthal D, Sattler FR, et al. The
       tolerance for Zidovudine plus thrice weekly or daily
       trimethoprim-sulfametnoxazole with and without leucovorirl
       for primary prophylaxis in advanced HIV disease. American
       Journal of Medicine 1995;98:177-182.

       B. Toxo--standard treatment

       * BACKGROUND

       One of the more common life-threatening brain infections seen
in patients with AIDS is toxo (toxoplasmosis). The parasite that
causes toxo (T. gondii) is found in "some birds and [other animals]
including humans." Humans become infected with the parasite while
they are in the womb or when they eat "raw or undercooked meat", or
accidentally eat feces from infected cats. People can also be
infected through blood transfusions. Although T. gondii can infect
the brain, other parts of the body - eye, heart, lung - may also
become infected.

       * SIGNS/SYMPTOMS OF TOXO

       As T. gondii "can infect any cell in the brain" patients can
have a variety of symptoms. Moreover, initial symptoms may be mild
at first but become worse over a period of weeks as the infection
spreads. Magnetic and X-ray scans of the brain can detect lesions
that suggest toxo. Signs/symptoms can include:

        seizures
        fever
        coma
        confusion
        problems understanding speech
        weakening 'arm strength'
        headache
        problems with speech/vision
        muscle control
        loss of control of muscles on one side of the body
        problems walking

       As CMI (cell-mediated immunity) weakens, the immune system is
less able to keep infections under control. As well, the parasite
that causes toxo seems able to further weaken cells of the immune
system when they find the parasite. Toxo is more likely to happen in
patients with less than 200 CD4+ cells. Some patients may have
anti-toxo antibodies in their blood and are at increased risk for
developing toxo.

       * STANDARD TREATMENT

       Patients usually receive a combination of 2 drugs-
pyrimethamine and sulphadiazine. On the first day doctors may
prescribe 200 mg/day of pyrimethamine which is later reduced to 50
or 75 mg/day. Patients may also receive sulphadiazine in doses of 4
to 6 grams/day. This therapy usually continues for 6 weeks. Doctors
may also prescribe between 5 and 10 mg/day of the B-vitamin folic
acid to protect the bone marrow from the toxicity of the
antibiotics. Sulphadiazine may also affect the kidneys. Some doctors
stop prescribing AZT because it may weaken the effect of
pyrimethamine.

       * CLINDAMYCIN AND OTHER DRUGS

       As some patients may not be able to tolerate sulpha drugs,
doctors may substitute 2.4 to 4.5 g/day of clindamycin for
sulphadiazine. In some cases clindamycin may be sent directly into
patients' veins especially if they have nausea and vomiting.
Treatment with Bactrim/Septra or Mepron may be useful for some
patients who cannot tolerate pyrimethamine.

       * MAINTENANCE

       Patients will need to keep taking antibiotics to suppress the
infection for the rest of their lives. For maintenance doctors may
use between 25 and 50 mg/day of pyrimethamine and between 2 and 4
g/day of sulphadiazine. Patients who cannot tolerate sulpha drugs
may use a minimum of 1200 mg/day of clindamycin. Some doctors
prescribe Bactrim/Septra 1 DS (double strength) tablet taken every
day or 3 days weekly. Others may use dapsone (75 to 300 mg/ week)
with or without pyrimethamine (50 to 200 mg/ week). Doctors may
prescribe between 1 and 15 g/day of clarithromycin with minocycline
100 to 200 mg/ day.

       * EXPERIMENTAL DRUGS

       A number of research teams are conducting laboratory
experiments with toxo-infected mice testing combinations of various
antibiotics. Promising combinations may include pyrimethamine with:

        clarithromycin or azithromycin or roxithromycin
        Mepron(R)/Wellvone(R)
        rifabutin and/or clindamycin and/or Mepron

       REFERENCES:

              1. Luft BJ, Hafner R, Korzum MS, et al.
       Toxoplasmic encephalitisin patients with the Acquired
       Immunodeficiency Syndrome. New England Journal of Medicine
       1993;329(14):995-1000.

              2. St. Georgiev V. Management of toxoplasmosis. Drugs
       1994;48(2):179-188

              3. Smith G. Treatment of infections in the patient
       with Acquired Immunodeficiency Syndrome. Archives of Internal
       Medicine 1994;154:949-973.

              4. New L and Holliman RE. Toxoplasmosis and Human
       Immunodeficiency Virus (HIV) disease. Journal of Antimicro-
       bial Chemotherapy 1994;33:1079-1082.

              5. Haque S, Khan I, Hague A and Caspar L. Impairment
       of tbe cellular immune response in acute murine
       toxoplasmosis: regulation of interleukin 2 production and
       macrophage-mediated inhibitory effects. Infection and
       Immunity 1994;62(7):2908-2916

              6. Alder J, Hutch T, Meulbroek J and Clement J.
       Treatment of experimental Toxoplasmic gondii infection by
       clarithromycin-based combination therapy with minocycline or
       pyrimethamine. Journal of Acquired Immunodefieieney Syndrome
       1994;7(11):1141-1148.

              7. Bran-Pascaud M, Chad F, Simonpoli A-M, et al.
       Experimental evaluation of combined prophylaxis againstmurine
       pneumocystosis and toxoplasmosis. Journal of Infectious
       Diseases 1994; 170:653- 658.

              8. Aerugo F, Silver T and Remington J. Rifabutin is
       active in murine model of toxoplasmosis. Antimicrobial Agents
       and Chemotherapy 1994;38(3):570-575.

       C. Toxo: treatrnent with clarithromycin and minocycline

       * STUDY DETAILS

       Doctors in this study used 6 men and 2 women, all
HIV-infected, having an average CD4+ cell count of 18 cells. All had
toxo and treatment with pyrimethamine, sulphadiazine and clindamycin
caused serious side effects. X-ray scans of their brains detected
lesions suggestive of toxo in 7 subjects. In one subject the
infection was in the lung.

       Six subjects received clarithromycin in doses ranging from
3/4 to 2 g/day and 200 mg/day of minocycline. Subjects received the
combination for an average of 9 weeks. During this period of time
they also received 75 mg/day of pyrimethamine. The researchers
reported results from 6 subjects.

       * RESULTS-SYMPTOMS

       Symptoms cleared in 4 subjects, 3 of whom had 'minimal' brain
infection according to the X-ray scans. The 4th subject also lost
symptoms and his X-ray scan revealed no lesions in the brain. The
researchers note that the recovery seen in these 4 subjects may have
been helped by their previous use of standard anti-toxo therapy. Two
of the remaining 6 subjects died while receiving anti-toxo
treatment. The cause of death was a bacterial infection in one
subject and HIV-damage to the brain of the other subject.

       * RESULT-MAINTENANCE THERAPY

       Surviving subjects received clarithromycin 1 to 1.5 g/ day
and between 100 and 200 mg/day of minocycline. Three subjects also
received 1 tablet of Bactrim/Septra (single strength). Researchers
monitored subjects for an average of 7 months. Five subjects did not
have further symptoms of toxo. The sixth subject who was also
supposed to be taking Bactrim/Septra had another bout of toxo and
the researchers suggest that he was not taking that drug. One
subject died from complications caused by a stroke about 7 months
after he recovered from toxo. Researchers reported no side effects
from the combination of clarithromycin and minocycline combination.
The study doctors stated that clarithromycin-minocycline may be an
option for subjects who have toxo and do not benefit from standard
therapy. As well, combination therapy seems to suppress the
infection once subjects recover. The researchers suggest that more
studies are needed to test regimens such as theirs for patients with
toxo.

       Other researchers in California are conducting experiments
and trying to understand why the immune system fails to keep the
parasite that causes toxo under control. Doctors in the USA have
recently reported their experience with minocycline. These doctors
gave their patient intravenous doxycycline (minocycline) 200 mg/day
in addition to intravenous clindamycin 900 mg 3 times daily and oral
pyrimethamine 50 mg/day. This combination allowed their patient to
recover from toxo.

       REFERENCES:

              1. La Casein F, Scapha D, Perron C, et al.
       Clarithromycin-minocycline combination as salvage therapy
       for toxoplasmosis in patients infected with Hurnan
       Immunodeficiency Virus. Antimicrobial Agents and
       Chemotherapy 1995;39(1):276-277.

              2. van de Ven ES, Vree T, Milkers W, et al. In vitro
       effects of sulfadiazine and its metabolites alone and in
       combination with pyrimethamine on Toxoplasma gondii.
       Antimicrobial Agents and Chemotherapy 1995;39(3):763-765.

              3. Indorf AS and Pogrom P. Use of doxycycline in the
       management of a patient with Toxoplasmic encephalitis. AIDS
       1995;8(1):1633-1634.

       D. Roxithromycin for MAC/TB and toxo

       * BACKGROUND

       Although there are several drugs that doctors can use to
treat and prevent the life-threatening lung infection PCP, the brain
infection toxo (toxoplasmosis), tuberculosis (TB), and MAC, all
these drugs have side effects. In some patients these side effects
are mild and in others they are not. Doctors are experimenting with
a variety of drugs to see which is right for their patients. In the
late 1980s doctors in Germany reported that treatment with between 2
and 3 grams/day of the antibiotic erythromycin was effective against
PCP. Researchers in the EU have been experimenting with drugs
'related' to erythromycin such as azithromycin and clarithromycin.
We now report on another related drug, roxithromycin.

       * STUDY DETAILS

       Researchers enrolled 52 HIV-infected adults (46 men, 6 women)
who had less than 200 CD4+ cells (the average was about 133 cells).
At the time subjects entered the study none had any life-threatening
infections. Researchers randomly assigned subjects to one of 3
groups or 'arms'. Eighteen subjects received 300 mg/month of aerosol
pentarnidine (AP), 17 others received a combination of aerosol
pentamidine and roxithromycin (300 mg 3 times daily once per week);
and another 17 subjects received roxithromycin in the same dose and
schedule as in the other group.

       * RESULTS

       Subjects given roxithromycin developed life-threatening
infections much later than subjects given AP. As well, subjects
given roxithromycin were also less likely to develop the
life-threatening brain infection toxoplasmosis. These 2 differences
were statistically significant; that is, not likely due to chance
alone. Subjects receiving roxithromycin were less likely to develop
TB and MAC infections. Fungal infections in the throat occurred
evenly among the groups of subjects. For the purposes of this report
we will include the subjects receiving the combination of AP and
roxithromycin with the others who received roxithromycin alone as
there were no statistically significant differences between the 2
groups. For the listing of deaths in this study we report the number
for each of the three arms.

       * INFECTIONS AND DEATH: WHO GOT PCP, TOXO, TB/MAC, AND WHO
         DIED?

       PCP:    3 subjects on AP
                1 subject on roxithromycin

       toxo:   5 subjects on AP
                1 subject receiving roxithromycin

       TB/MAC: 4 subjects on AP
                No subjects on roxithromycin

       Deaths: 4 subjects on AP
                3 subjects on AP and roxithromycin
                3 subjects on roxithromycin

       * TOXICITY

       Doctors found that AP was 'well tolerated' by subjects.
Researchers had to stop giving roxithromycin to 5 subjects who had
"nausea, abdominal pain and skin allergies" and to 1 other subject
who had high blood levels of liver enzymes suggesting some liver
damage. Upon investigation the researchers found that this last
subject had hepatitis C which may have caused the high levels of
liver enzymes. They noted that this subject suffered no symptoms of
liver (or any other) toxicity. Six weeks after he stopped taking
roxithromycin his liver enzyme levels fell to normal. As soon as
subjects developed life-threatening infection(s), researchers
stopped giving them roxithromycin. Causes of death in this study
included various bacterial infections, unintentional weight loss and
one case of toxo. No subject died from PCP, TB or MAC infection.

       * ROXITHROMYCIN

       As many people in Western Europe have greater exposure to the
parasite that causes toxo, it is interesting that more subjects
receiving roxithromycin did not develop symptoms of toxoplasmosis.
The researchers suggest that another study with more patients should
be conducted to confirm their findings. Based on their data the
researchers suggest that roxithromycin 900 mg/day once a week
protects subjects for at least 8 months from developing toxo. The
researchers note that the proportion of subjects who stopped taking
roxithromycin because of toxicity is similar to withdrawal rates
seen in other trials using Bactrim/Septra as PCP prevention.
Roxithromycin in this study was supplied by Roussel-Uclaf.

       REFERENCES:

              1. Durant J, Hazime F, Carles JM, etal. Prevention of
       Pneumocystis carinii pneumonia and of cerebral toxoplasmosis
       by roxithromycin in HIV-infected patients. Infection 1995;23
       (supplement 1 ):s533- sS38.

       E. Predicting who will get toxo

       * STUDY DETAILS

       Researchers in France used data collected on 499 subjects to
try and find out which subjects would develop the life-threatening
brain infection toxo. At the time these subjects entered the study
none had toxo. The average CD4+ cell count was 70 cells. About 60%
of subjects had less than 50 CD4+ cells. Technicians tested the
blood samples from 410 subjects to find antibodies against toxo. A
total of 298 had anti- toxo antibodies. When subjects entered the
study 80 received Bactrim/Septra as preventative therapy against
PCP/toxo; '34 received pyrimethamine'; 19 received dapsone; '11
received [Fansidar@]' and 1 received pyrimethamine-sulphadiazine.

       * RESULT-SURVIVAL

       Researchers monitored subjects for an average of 1 year
during which 16% (83) subjects developed toxo; 75 had it as a brain
infection, 7 had the infection in their eyes and 1 developed toxo in
the lungs. Altogether, 67% of the 499 subjects died while in this
study.

       * CD4+ CELL COUNTS

       In this study subjects with CD4+ cell counts of less than 100
cells were at high risk for developing toxo. This link between low
CD4+ cell eounts and toxo was statistically significant; that is,
not likely due to chance alone. When subjects developed toxo they
had an average CD4+ cell count of 31 cells. About 18% of subjects
who had less than 100 CD4+ cells when they entered the study
developed toxo. By contrast, only 9% of subjects who entered the
study with CD4+ cell counts of at least 100 cells developed toxo.

       * ANTIBODIES

       Subjects who had anti-toxo antibodies in their blood were
very likely to develop toxo while in the study. Over a period of 1
year 21% of these subjects developed toxo compared to none of the
subjects without these antibodies. This difference was statistically
significant.

       * BACTRIM/SEPTRA REDUCES THE RISK

       "Three of 80 [subjects] receiving Bactrim/Septra and 72 of
419 subjects not receiving Bactrim/Septra developed toxo in their
brains". This was statistically significant. "One of 34 [subjects]
receiving pyrimethamine and 74 of 465 subjects who [did not use]
pyrimetharnine when they entered the study developed toxo." This
difference was also statistically significant.

       * CHECKING THE RISKS

       There were 149 subjects with less than 100 CD4+ cells who had
anti-toxo antibodies but did not receive antibiotics. Forty-eight
(32%) of these subjects developed toxo in their brains. Of the 74
subjects with less than 100 CD4+ cells who had antibodies against
toxo but did receive antibiotics, 5 (7%) developed toxo in their
brain. This difference was also statistically significant.

       * SURVIVAL

       All subjects who developed toxo died at some point during the
study. Taking antibiotics did not seem to affeet survival. When
researchers adjusted their ealeulations to take into aceount
different CD4+ eell eounts, again there was no difference in
survival.

       REFERENCES:

              1. Oksenhendler E, Charreau I, Tournerie C, et al.
       Toxoplasma gondii infection in advanced HIV infection. AIDS
       1994;8:483-487.

       III  TOXICITY

       A. Caution about thalidomide

       * A WARNING

       Researchers at Cambridge University have been conducting
experiments on healthy humans, 10 of whom received the tranquilizer
thalidomide 200 mg/day and 6 others who did not. Results of
immunologic tests clearly showed that thalidomide appear to
'switch' the immune response to one based on humoral immunity where
antibody-producing B-cells play a major role. This 'switch' may, in
the long term, eause serious eonsequences. For details please see
TreatznentUpdate 56. The Cambridge researchers warn that thalidomide
may weaken the immune system's ability to fight life-threatening
infections.

       REFERENCES:

              1. McHugh SM, Rifkin R, Deighton J, et al. The
       immunosuppressive drug thalidomide induces T helper cell type
       2 (Th2) and concomitantly inhibits Th1 cytokine production
       in mitogen-and antigen-stimulated human peripheral blood
       mononuclear cell cultures. Clinical and Experimental
       Immunology 1995;99:160-167.

       B. Reducing the toxicity of sulpha drugs

       * BACKGROUND

       Sulpha drugs are often the first therapies doctors consider
when treating HIV-infected patients with the life-threatening lung
infection PCP or the brain infection toxo (toxoplasmosis).
Unfortunately many patients with HIV/AIDS tend to 'experience'
serious side effects when given these drugs. Researchers are not
sure why this happens. It may be that the way HIV-infected subjects
'process' drugs leads to the production of compounds that cause
these side effects.

       * ANTIOXIDANTS

       In laboratory experiments with cells, treatment with
antioxidants appears to reduce the production of toxic compounds
from sulpha drugs. This may not be surprising because several
research teams have reported that subjects with HIV/AIDS have
less-than-normal levels of certain substances used by the body to
make its detoxifying enzymes. Researchers and their patients are
experimenting with a number of antioxidants that the body cannot
make (vitamins C and E and beta carotene) and taking supplements of
materials (sulphur-containing amino acids - cysteine, methionine,
the minerals selenium, copper, manganese and zinc) needed to make
the body's antioxidant enzymes. Some researchers are conducting
experiments where at first subjects receive small doses of sulpha
drugs which gradually increase to the full treatment dose--a process
called desensitization.

       C. Experiments in France

       * DOSE

       Researchers in Paris reported results from 8 men and 4 women
whose average CD4+ cell count was about 100 cells. These subjects
had been using Bactrim/Septra (containing 160 mg of trimethoprim and
800 mg of sulphamethoxazole) to prevent infections such as PCP/toxo
(11 of them were taking 160/800 - one double strength tablet as PCP
prevention). The remaining subject took a 'treatment' dose (640 mg
trimethoprim/ 3200 sulphamethoxazole mg/day). Half of the subjects
developed side effects within 15 days of using Bactrirn/Septra.
Eleven subjects had a rash without fever or [puritis].

       * THE PROTOCOL

       The researchers kept the subjects in hospital for 2 days so
that if a life-threatening reaction to Bactrim/Septra occurred,
subjects' lives could be saved. Researchers started giving subjects
small doses of liquid Bactrim/Septra every 3 hours. The first dose
had 0.2 mg of trimethoprim and 1 mg sulphamethoxazole. Eventually
subjects would take 80 mg trimethoprim and 400 mg/day of
sulphamethoxazole (both drugs) once daily. The researchers did not
raise the dose of Bactrim/Septra nor did subjects receive any new
drug for the first month after they had been desensitized. Subjects
did not receive any antihistamines or corticosteroids.

       * RESULTS

       Four subjects developed side effects - rash - despite the
desensitization protocol. Another 4 subjects developed side effects
within the first month after being desensitized. Ten months after
being desensitized only 4 subjects could continue to use
Bactrim/Septra. Researchers could not understand why some subjects
remained desensitized. They checked the CD4+ cell counts amongst the
subjects but there were no statistically significant differences.
This research team suggests that a longer period of desensitization
may be more useful.

       REFERENCES:

              1. Bachmeyer C, Salrnon D, Guerin C, et al.
       Trimethoprim-sulphamethoxazole desensitization in
       HIV-infected patients: an open study. AIDS 1995;9(3):299-300

              2. Rieder MJ, Krause R, Bird LX and Dekaban G.
       Toxicity of sulfonamide-reactive metabolites in HIV-infected
       HTLV-infected, and non-infected cells. Journal of Acquired
       Immunodeficiency Syndromes and Human Retrovirology
       1995;8(2):134-140.

       IV TESTING

       A. Using skin tests to predict infections

       * BACKGROUND

       In general, most HIV-infected people have decreasing numbers
of CD4+ cells over time. Measuring CD4+ (and CD8+) cell counts can
be useful because doctors can make decisions about when to begin
giving patients drugs to prevent certain infections. By themselves,
CD4+ cell counts do not provide a detailed report on the ability of
the immune system to resist infections. Many of the life-threatening
infections seen in AIDS occur because T cells have lost a very
important defense - CMI (cell-mediated immunity). CMI is
particularly useful in fighting microbes that can infect and 'hide'
inside cells. In such cases, antibodies alone will not be useful and
may even help spread the infection. Counting CD4+ cells may provide
a sense of certainty; something which people can grasp and easily
understand. Performing skin tests may not give people that same
sense of precision. Nonetheless, skin testing is one of the few ways
to measure CMI.

       * WHICH SKIN TESTS?

       Nurses injected a small amount of protein from various
microbes under the skin. In subjects with normal levels of CMI,
within 48 to 72 hours after the injection there is a reaction at the
injection site. The reaction is usually swelling and redness and the
skin becomes raised. This delayed reaction is why these tests are
called DTH (delayed-type hypersensitivity). In subjects who have
lost some level of CMI the reaction may be reduced. In subjects with
very low levels of CMI there may be no reaction. The immune system
of these subjects (no reaction) is described by researchers as
'anergic' or exhausted. If performed over a period of time skin test
results can reveal what is happening to the body's ability to
produce CMI. For this study, researchers decided that subjects whose
skin produced a 10 mm by 10 mm reaction to the injection of protein
(from microbes) had a 'positive' reaction.

       * STUDY DETAILS

       Researchers at military bio-medical centres in the USA have
been conducting experiments on HIV-infected subjects. In one
experiment researchers conducted extensive laboratory tests on
subjects over a five-year period - 1985 to 1990. In this experiment
researchers also measured CMI using skin tests. The study doctors
analysed data on 600 subjects, 94% of whom were male and 6% female.
Their average age was 28 years. At some point during their study 28%
of subjects used AZT.

       * RESULTS

        about 60% of subjects who had less than 200 CD4+ cells were
         completely 'anergic'; their level of CMI was extremely low.

        approximately '96% of [subjects] with more than 400 CD4+
         cells had [some level of CMI]' These subjects reacted to
         'at least one skin test'. These differences in levels of
         CMI were statistically significant; that is, not likely due
         to chance alone.

        '86% of subjects with more than 400 CD4+ cells were able to
         [react] to at least 2 skin tests compared to '45% of
         subjects' with less than 400 CD4+ cells.

        on average, subjects who could only react to 1 of the 5
         proteins (with which they had been injected) had reduced
         levels of CD4+ cells compared to subjects who had '2 or
         more [skin reactions]'. Again, this difference was
         statistically significant. Researchers looked at skin test
         results and compared them to the appearance of
         life-threatening infections. They found that subjects who
         had the following test results developed a life-threatening
         infection/cancer in the following time:

        no positive tests - 43 months

        1 positive result - 51 months

        2 or more positive tests - 55 months

       These differences in time to infections/cancers were
statistically significant. As well, DTH responses were clearly
linked to the development of AIDS even in subjects who had
relatively high CD4+ cell counts when they entered the study.
Moreover, skin test responses alone could be used to predict which
subjects would develop AIDS.

       * OTHER GROUPS

       Some researchers think that other groups of HIV-infected
subjects, such as drug users, may have weaker CMI than (in this
study) gay/bisexual men, and that this population may have different
skin test results. Other researchers suggest that a smaller
measurement (5 mm x 5 mm) could have been used as a cut-off point.
In the article below we report results on gay/ bisexual men, drug
users (both HIV-infected and non-HIV-infected) as well as
heterosexual women.

       REFERENCES:

              1. Blatt SP, Hendrix CW, Butzin CA, et al.
       Delayed-type hypersensitivity skin testing predicts
       progression to AIDS in HIV-infected patients. Annals of
       Internal Medicine 1993;119(3):177-184.

       B. Skin tests on HIV-infected and non-HIV-infected people

       * TESTING FOR TB

       As part of tuberculosis (TB) control programmes in the USA,
public health workers perform a variety of tasks such as making sure
that their patients take their antibiotics as instructed, providing
counselling and testing their patients to see if they have been
infected with the bacteria that cause TB. Nurses can inject a small
amount of protein from TB-causing bacteria called PPD (purified
protein derivative) and watch for a reaction 2 days later. This
reaction is called delayed-type hypersensitivity (DTH). A reaction
to PPD, swelling and redness indicates that the person has been
exposed to TB-causing bacteria or has been vaccinated with the TB
vaccine BCG. This reaction depends on one type of immune response
caUed CMI (cell-mediated immunity).

       * ANERGY

       Under constant attack by HIV and other microbes over many
years CMI weakens and infections grow out of control. In people with
weak or 'exhausted' immune systems there may be no reaction to PPD
or other proteins and these people are called 'anergic'. This lack
of reaction to PPD creates problems for health care workers when
trying to find out if their patients have been infected with TB. One
way to try and deal with this problem of no reaction to PPD is to
also inject them with 'at least 2 [other proteins that cause DTH
reactions)'. In practice this means that health care workers inject
patients with proteins from bacteria, fungi or viruses at the same
time they receive PPD injections (each in its own spot on skin). In
this way if patients react with swelling and redness to the other
proteins but don't react to PPD, it is very likely that they have
not been infected by TB-causing bacteria (these patients do not have
symptoms of TB). To test this idea, researchers across the USA have
been performing tests of DTH on a variety of subjects for which we
provide details.

       * STUDY DETAILS

       Over a 1 6-month period researchers enrolled over 1,300
subjects and here is the subject profile at the start of the study:

        86% male
        70% gay/bisexual
        25% injection drug users
        5% heterosexual women
        68% white, 24% black and 6% hispanic
        50% of HIV-infected subjects had a CD4+ cell count
         of 410 cells
        For 50% of non-HIV-infected subjects the equivalent
         was 889 cells

       Although most of the subjects were HIV-infected, researchers
enrolled a smaller but similar group of non-HIV-infected subjects to
use for comparison.

       * RESULTS

        as expected, non-HIV-infected subjects were more likely to
         have DTH than HIV-infected subjects, a difference that was
         statistically significant

        HIV-infected and non-infected injection drug users had
         similar rates of DTH reactions to PPD

        Injection drug users (both HIV-infected and non- infected)
         were 3 times more likely to have a reaction to PPD than
         gay/bisexual men. This difference was statistically
         significant.

        Among non-HIV-infected subjects, anergy (a lack of
         responses to the various proteins used) occurred in 44% of
         injection drug users and 16% of gay/bisexual men. This
         difference between the 2 groups was statistically
         significant

        A lack of response to all 4 proteins (anergy) occurred in
         the same proportion of subjects across all groups of
         HIV-infected subjects.

        About 11% of heterosexual women had DTH to PPD

        non-HIV-infected gay/bisexual men were 3 tirnes more likely
         to have DTH to PPD compared with similar HIV-infected men.
         This difference was also statistically significant.

       * CD4+ AND DTH

       There was a general trend for fewer DTH responses as CD4+
counts fell among HIV-infected subjects. This trend was
statistically significant.

       * FOCUS ON TB

       In this study, among 716 subjects (who received all 4
microbial proteins) there was no link between responding to PPD and
reactions to other proteins tested. Older subjects, and those who
received the TB vaccine BCG or who had reacted to PPD in the past
were more likely to have a 'positive' skin test result to PPD. No
subject with less than 100 CD4+ cells reacted to PPD in this study.

       * FOCUS ON AN EXHAUSTED IMMUNE SYSTEM (ANERGY)

       The researchers in this study found that anergy was more
likely to occur in:

        HIV-infected subjects
        HIV-infected subjects with less than 200 CD4+

       Anergy was less likely to occur in:

        HIV-infected subjects with at least 600 CD4+ cells
        non-HIV infected subjects

       The researchers found that 'overall, HIV-infected [injection]
drug users were no more likely to be anergic than HIV-infected
gay/bisexual men'.  Women did not seem to be any more anergic than
men. Interestingly, results from this study were similar to another
which used data from over 2,000 Haitian subjects. There are problems
comparing results from studies which used different tests and
different ways of interpreting skin test results.

       * DEVELOPING TB

       According to the study doctors, results from earlier studies
'suggest that many HIV-infected people have a positive [reaction to
PPD injections] months to years before [symptoms of TB appear].'
They add that 'most cases of TB develop [when patients can react to
skin tests using PPD].' They add that most cases of HIV-related TB
are caused by reactivated and not new infections.

       * WHAT TO DO?

       Testing anergic subjects with other proteins might spare some
people from being given anti-TB medication (assuming that these
people had been TB-infected despite a negative reaction to PPD)
isoniazid and its toxicities. The researchers found that subjects
were likely to react to PPD regardless of any other reaction to
other proteins. In this study, anergy to PPD started when
subjects' CD+ cell counts fell below 400 cells. The study doctors
suggest that in the absence of highly accurate tests that can
predict who will get TB, better ways of detecting TB bacteria and
less toxic therapies, early skin (in HIV-infected subjects) should
be done on a regular basis 'even in patients with low CD+ cells'.
Skin testing kits, such as the 'Multitest', sold by Pasteur-Merieux
Serum et Vaccins.

       REFERENCES:

              1. Markowitz N, Hansen NI, Wilcosky TC, et al.
       Tuberculin and anergy testing in HIV-seropositive and
       HIV-seronegative persons. Annals of Internal Medicine
       1993;119(3):185-193.

       Copyright (c) 1995 - Treatment Update.  Noncommercial
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       gateway to a world of people, knowledge, and resources.
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