       TreatmentUpdate 58 - Volume 7, No. 4 - April 1995
       *************************************************
       published by Community AIDS Treatment Information
       Exchange, Suite 420 - 517 College St., Toronto,
       Ontario, Canada M6G 4A2
       *************************************************

       I      IMMUNOMODULATORS

       A. Promising results: IL-2 and AZT

       * STUDY DETAILS--PART 1

       Researchers in the USA (National Institutes of Health,
Bethesda, Maryland) enrolled a small group of HIV-infected subjects
for their experiments with the immune booster IL-2. (For background
information on therapy with interleukins and related chemicals,
please read TreatmentUpdate 56). In the first part of their study 23
subjects with CD4+ cell counts above 400 cells went into a hospital
for 3 weeks to receive intravenous IL-2. The study doctors did not
provide details on age, CD8+cell count or gender of the subjects.
During their stay in the hospital, subjects received increasingly
high doses of IL-2 ranging between 1.8 million international units
(IU) and 24 million IU/day. The subjects were supposed to be taking
AZT 500 to 1200 mg/day for 6 weeks before receiving IL-2.

       * STUDY DETAILS--PART 2

       Researchers enrolled a group of 10 subjects (8 men, 2 women)
for this experiment. The average CD4+ cell count was about 400
cells. Subjects in this part of the study received IL-2
intravenously for 5 days at doses ranging as high as 18 million
IU/day to doses as low as 6 million IU/day. At the end of the fifth
day which the researchers called a 'course', subjects did not
receive another course for 2 months at which time another 5-day
infusion of IL-2 was followed by another 2 month 'rest'. All
subjects received a minimum of 4 courses, some as many as 13
courses. Most subjects in this part of the study received AZT 500
mg/day or, the related drugs ddC and/or ddI either "alone or in
combination."

       *  STUDY DETAILS--PART 3

       Another 15 HIV-infected subjects with CD4+ counts of 200 or
less enrolled in this part of the study. They received IL-2
intravenously and took anti-HIV drugs by mouth (AZT, ddC, ddI)
"alone or in combination".

       * RESULTS--PART 1: TOXICITY

       Subjects receiving high doses of IL-2 experienced side
effects including severe muscle/bone pain, fever, fatigue, build-up
of water causing swelling, low blood levels of platelets and a type
of white blood cells called neutrophils. Lab tests detected liver
and kidney damage. There were no large changes in CD4+ cell counts
or production of virus in this group.

       * RESULTS--PART 2: TOXICITY

       Subjects experienced similar side effects as above. Less
common side effects included depression and 'altered perception'
(the researchers did not explain the precise meaning of this term in
these subjects). Eight of 10 subjects in this group had such severe
side effects that doctors had to reduce their dose of IL-2.

       - CD4+and CD8+cells

       In 6 of the 10 subjects CD4+cell counts doubled. The average
CD4+ cell count climbed to over 900 cells by the 9th month of the
trial. The CD8+cell counts remained stable. In 2 subjects the
CD4+cell counts did not increase dramatically. These 2 subjects
later developed the life-threatening lung infection PCP.

       - Virus

       Tests of blood cells from these subjects suggested that there
was a small and temporary increase in production of HIV after they
received each infusion of IL-2. In 4 other subjects viral production
did not appear to increase.

       * RESULTS--PART 3: TOXICITY

       Although 15 subjects entered this part of the study
researchers reported data on 12 subjects. In general, side effects
caused by IL-2 were severe in this group of subjects. One of the 15
subjects who was also using compound Q died "2 days after receiving
a third dose of IL-2". Information from this subject was not used in
the data analysis.

       - CD4+ cells

       The researchers divided this group into 2 sub-groups: 6
subjects with CD4+cells "initially between 100 and 200 cells"
received IL-2 and only 2 of these subjects had an increase in their
CD4+ cells of at least 50%. In the other group of 6 subjects with
counts less than 100 CD4+ cells, none "had increased CD4+ cell
counts."

       - Virus

       On average, the production of HIV in the white blood cells of
the 12 subjects appeared to double when they received IL-2. Two
subjects with less than 100 CD4+ cell counts developed
life-threatening infections and later died (the researchers did not
release details).

       Based on the results from the 6 subjects with large increases
in their CD4+ cell counts, it is not clear if these subjects
compared to similar subjects who did not have this increase will
have:

       - improved quality of life
       - decreased chances of life-threatening infections/cancers
       - improved survival

       There are some issues about using chemicals such as IL-2
that readers may wish to consider. These appear in the
section below.

       REFERENCE:

              1. Kovacs JA, Baseler M, Dewar RJ, et al. Increases in
       CD4+ T lymphocytes with intermittent courses of interleukin-2
       in patients with Human Immunodeficiency Virus infection: a
       preliminary study. New England Journal of Medicine
       1995;332(9):567-575.

       B. IL-2 issues to consider

       Although the results from the small study of IL-2 appear
promising, there are some issues that doctors who treat patients
infected with HIV/AIDS may wish to consider before giving their
patients this immune booster which is already licensed for the
treatment of kidney cancer.

       * CD4+ CELLS, VIRUS

       Most of the body's lymphocytes are in lymph nodes and
tissues. Moreover, most HIV is also located in those tissues. It is
true that researchers saw increases in CD4+ cells from blood samples
taken from subjects. These increases may or may not have happened in
the lymph nodes/tissues. Much viral replication takes place in the
lymph nodes/tissues and researchers need to find out if IL-2
infusions affected production of HIV in those tissues. In work
carried out in lab of NIH researcher/administrator Dr. Tony Fauci,
IL-2 seems to increase viral replication in cells infected with the
virus.

       * EXHAUSTED CELLS

       Other researchers have documented the effects that high doses
of IL-2 can have on cells of the immune system. In one of several
studies, doses of 18 million IU/day resulted in T cells that did not
respond normally when they encountered microbes. The T cells from
these experiments had become 'exhausted' as a result of too much
IL-2.

       * WHAT KIND OF IMMUNITY?

       Under constant attack by HIV over many years, the immune
system changes its response to that infection. It appears that the
immunity needed to control microbes such as CMV, MAC, and the
various yeast and parasitical infections, is weakened. This type of
immune response is called CMI (cell-mediated-immunity). Some
researchers think that giving patients chemicals such as
interferon-gamma, IL-2 and IL-12, may help restore some level of
CMI. Researchers do not know the best dose or 'mix' of cytokines
(interferons, interleukins) to give patients so a number of trials
are underway testing various doses and combinations. The chemicals
that boost CMI weaken the other arm of the immune system (called
humoral immunity) that uses chemicals such as IL-4, -6 and -10.
Chemicals that strengthen humoral immunity weaken CMI. In
experiments on subjects without HIV infection in the USA, IL-2
appears to boost humoral immunity. It will be interesting to see the
results of immunologic tests from HIV-infected subjects who are also
treated with IL-2 to see if their CD4+cells:

       - are able to respond effectively to attack by microbes
       - produce cytokines that help the immune system contain
         infections.

       * COST ISSUES

       IL-2 is not cheap; "each 5 day infusion" costs about $2,500
US. Moreover, subjects had to be placed in a hospital for that
length of time; costing yet more money. The researchers plan to use
lower doses of IL-2 in further tests hoping to reduce the toxicity
of the drug. As well, they want to see if subjects can benefit from
injections of IL-2 under the skin.

       REFERENCES:

              1. Kinter AL, Poli G, Fox L, et al. HIV replication in
       IL-2 stimulated peripheral blood mononuclear cells is driven
       in an autocrine/paracrine manner by endogenous cytokines.
       Journal of Immunology 1995; 154:2448-2459.

              2. Clementi E, Bucci E, Citterio G, et al. Reversible
       anergy in circulating lymphocytes of cancer patients during
       IL-2 therapy. Cancer Immunology and Immunotherapy
       1994;39:167-171.

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

              4. Cunningham-Rundles C, Kazboy K, Hassett J, et al.
       Brief report: enhanced humoral immunity in common variable
       Immunodeficiency after long-term treatment with polyethylene
       glycol-conjugated interleukin-2. New England Journal of Medi-
       cine 1994;331(14):918-921.

              5. Mocci S and Coffman RL. Induction of the Th2
       population from a polarized Leishmania-specific Th1
       population by in vitro culture with IL-4. Journal of
       Immunology 1995;154:3779-3787.

       C. Vitamin E for HIV/AIDS?

       For background details on production of cytokines in HIV/AIDS
please see the section above.

       * VITAMIN E BACKGROUND

       Vitamin E dissolves in fat and together with trace minerals
such as selenium and copper, works with antioxidant enzymes to
protect the body from highly active molecules called free radicals.
This vitamin also plays a key role in maintaining the effectiveness
of the immune response.

       * MICE WITH AIDS

       Mice infected with a certain retrovirus (LP-BM5) become ill
and develop symptoms of AIDS (MAIDS). Infected mice often have
swollen spleens, persistently swollen lymph nodes and tissues, high
blood levels of unnecessary antibodies. As well, MAIDS mice appear
to release higher-than-normal levels of IL-4 and IL-6 while making
less of IL-2 and interferon-gamma. Eventually, mice with MAIDS die.
Researchers in the USA have been performing experiments with mice
given high doses of vitamin E to see if this could help mice with
AIDS.

       * VITAMIN E FOR THIS STUDY

       Researchers used the following form of vitamin E
d-alpha-tocopherol acetate. Some mice were infected with the virus
that causes MAIDS and others were not. Vitamin E was given to some
mice but not others. Researchers conducted the experiment for 16
weeks.

       * RESULTS

       - antibodies; infected mice receiving vitamin E produced
         fewer unnecessary antibodies than infected mice not given
         the vitamin. This effect continued into the 12th week of
         the study after which antibody levels rose to levels seen
         in infected mice not given vitamin E.

       - swollen spleens; infected mice given vitamin E had swollen
         spleens but these were 2 to 3 times smaller than infected
         mice not given the vitamin. This difference between the 2
         groups was statistically significant and lasted through the
         16th week of the study.

       - IL-2; cells of the immune system from infected mice
         produced reduced levels of the cytokines IL-2 and
         interferon-gamma compared with similar cells from
         uninfected mice. Infected mice who received vitamin E had
         increased production of those 2 cytokines compared to
         infected mice not given vitamin E. Production of IL-2 in
         vitamin E-treated and infected mice reached its highest
         level 12 weeks after infection after which it fell.

       - IL-4; vitamin E-treated mice with MAIDS produced low levels
         of IL-4 while untreated and infected mice made higher
         levels of this cytokine.

       - IL-6; vitamin E-treated mice with AIDS did not produce as
         much IL-6 as untreated animals with MAIDS.

       * VITAMIN E IN HUMANS

       The results reported here appear promising. While humans AIDS
and MAIDS are both caused by retroviruses, the viruses are not
closely related. Researchers do not fully understand the long-term
interaction between HIV and the human immune system. Results seen in
mice with vitamin E (or any other treatment) may not necessarily
appear in humans with AIDS. These data from this study are promising
and may serve as a guide when designing studies in people with
HIV/AIDS. In addition to its effect on the immune system, vitamin E
may protect cells from highly active molecules called 'free
radicals'. According to researcher Chester Myers, 'the known decline
in body antioxidant levels over time argues strongly for extra
intake of at least certain antioxidants [such as beta carotene C
and E]'. For information on the importance of vitamin E in human
nutrition please see the section on nutrition. To read about the
safety of vitamin E please see the section on toxicity.

       REFERENCES:

              1. Clerici M and Shearer G. The Th1-Th2 hypothesis of
       HIV infection: new insights. Immunology Today
       1994;15(12):575581.

              2. Sonnerborg A, Carlin G, Akerlund B and Jarstrand C.
       Increased production of malondialdehyde in patients with
       Human Immunodeficiency Virus infection. Scandinavian Journal
       of Infectious Diseases 1988;20:287-290.

              3. Greenspan HC and Aruoma OK. Oxidative stress and
       apoptosis in HIV infection: a role for plant-derived
       metabolites with synergistic antioxidant activity. Immunology
       Today 1994;15(5):209-213.

              4. Wang Y, Huang DS, Eskeison CD and Watson RR.
       Long-term dietary vitamin E retards development of
       retrovirus-induced disregulation in cytokine production.
       Clinical Immunology and Immunopathology 1994;72(1):70-75.

              5. Wang Y and watson RR. vitamin E supplementation at
       various levels alters cytokine production by thymocytes
       during retrovirus infection causing murine AIDS. Thymus
       1994;22:153-165.

              6. Wang Y and watson RR. Potential therapeutics of
       vitamin E (tocopherol) in AIDS and HIV. Drugs 1994;48(3):327.

       D. AZT and MAC

       * BACKGROUND

       In this report we present findings from Western Australia
where doctors have been monitoring the effect of AZT on the immune
system of subjects with AIDS. Their results suggest that AZT can
temporarily boost the immune response (cell-mediated immunity)
against MAC (Mycobacterium avium complex).

       * STUDY DETAILS

       The bacteria that cause TB are related to MAC. Researchers
injected a small amount of protein from TB-causing bacteria (called
tuberculin) under the skin of subjects. b some subjects, within 48
hours the skin at the injection site would turn red and slightly
swollen and become raised. Ordinarily this reaction might suggest
that the subjects had encountered TB-causing bacteria. However, over
90% of subjects in this study had received the anti-TB vaccine BCG
and no subject developed TB before or during this study.

       * TESTING FOR CMI

       As part of an overall measure of CMI, nurses injected small
amounts of protein from 7 microbes (including TB-causing bacteria)
under the skin of subjects on a regular basis. The researchers
decided that a subject had a 'positive' reaction if the swollen skin
had a diameter of at least 2 mm. Nurses then added the various
diameters caused by the other injections and produced an average
number or 'score'.

       * CHECKING THE SCORE

       Researchers reviewed hospital records and found 114 subjects
whose score fell below 5 mm before they received AZT. Of the 114
subjects, 110 did not react (with swelling or redness) when injected
with TB protein. This suggested that the immune system of those
subjects could no longer identify and destroy TB-causing bacteria.
As the 110 subjects began to take AZT, 49 had an increase of more
than 5 mm in their average score suggesting an improvement in CMI.

       * RESPONDERS

       In a detailed review of the skin-testing scores, the
researchers found that 20 of the 49 subjects did not have a reaction
to TB protein. The researchers called these subjects 'non
-responders' while the 29 that did respond they called 'responders'.
Responders had an average CD4+ cell count of 73 cells, while the
non- responders had 178 cells. This difference between the 2 groups
was statistically significant.

       * WHO GETS MAC?

       The researchers found that "none of the non-responders
developed [widespread] MAC infection during the study period." In
contrast, 50% of responders developed life-threatening MAC infection
24 months after they started to use AZT. By the 40th month all
responders developed life-threatening MAC infection. These
differences between the non-responders and responders were
statistically significant and remained so even when researchers
adjusted their calculations to take into account CD4+ cell counts.

       According to the researchers "all [subjects] with [life-
threatening MAC infection]" lost their skin reactions to all of the
microbes used in skin testing. This change suggests a huge loss of
CMI. When researchers looked at who developed PCP, fungal infections
of the brain or Kaposi's sarcoma they did not find any
statistically significant differences between the two groups. The
researchers did find that as the responding subjects' CD4+ cell
count fell to nearly zero the chance of a subject testing 'positive'
to TB protein rose to nearly 100%.

       * AZT BENEFIT

       Treatment with AZT appeared to boost levels of CMI in general
in these subjects. CMI reached its highest level at 3 months after
subjects began using AZT and then fell. Similarly, levels of CMI
against TB protein peaked around the 3rd month in responding
subjects and then declined. It appeared that once CMI was increased
in the responders, the immune system could detect infection with MAC
and begin to mount a response. Indeed, some subjects developed
"fevers, [night sweats, unintentional weight loss, persistently
swollen lymph nodes]." The doctors think that some patients have a
low-grade MAC infection but only develop symptoms if:

       - CMI against MAC is restored
       - the MAC infection becomes overwhelming

       The researchers suggest that the loss of improved CMI is due
to the toxicity of AZT. Another research team in France studying the
effect of AZT on CMI reached the same conclusion.

       REFERENCES:

              1. Mallal SA, James IR and French MAH. Detection of
       subclinical Mycobacterium avium intracellularae complex
       infection in immunodeficient HIV-infected patients treated
       with Zidovudine. AIDS 1994;8(9): 1263-1269

              2. French MAH, Mallal SA and Deacons R.
       Zidovudine-induced restoration of cell-mediated immunity to
       mycobacteria in immunodeficient HIV-infected patients. AIDS
       1992;6(11):1293- 1297.

              3. French MAH, Cameroon P, Grimsley G, et al.
       Correction of Human Immunodeficiency Virus-associated
       depression of delayed-type hypersensitivity (DTH) after
       Zidovudine therapy: DTH, CD4i T cell numbers, and epidermal
       Langerhans cell density are independent variables. Clinical
       Immunology and Immunopathology 1990;55 :86-96.

              4. Dadaglio G, Langlade-de Moyen P, et al. Enhancement
       of HIV- specific cytotoxic T lymphocyte response by
       Zidovudine (AZT) treatment Clinical and Experimental
       Immunology 1992;87:7-14.

	II  INFECTION FIGHTERS

       A. High-dose acyclovir--not for CMV

       * BACKGROUND

       Some doctors prescribe high doses of acyclovir (Zovirax(R);
up to 4.8 grams/day) because they think that it may protect their
patients from the sight-threatening infection CMV retinitis.
Researchers in the USA have been testing combinations of AZT and
acyclovir in subjects with HIV infection. These researchers have
recently released some results from their experiments.

       * STUDY DETAILS

       Subjects in this study had symptoms of HIV infection and a
CD4+ cell count of at least 200 cells when they entered the study.
Researchers did not release detailed information about the subject
profiles. Fifty-one subjects received at random AZT 600 mg/day and
acyclovir 800 mg/6 times daily, while 41 others received AZT 600
mg/day and placebo. All drugs were taken orally. Technicians tested
urine samples for CMV. Researchers monitored subjects for about 1
year.

       * RESULTS

       Subjects receiving high-dose acyclovir did not appear to have
any statistically significant decline in production of CMV compared
to subjects not receiving acyclovir. CMV taken from subjects on
acyclovir did not become resistant to the related drug ganciclovir
(Cytovene@, DHPG). At this time, the researchers did not provide any
details on the development of CMV retinitis that may have happened
to subjects who received further monitoring.

       REFERENCE:

              1. Drew WL, Anderson R, Lang W, et al. Failure of
       high-dose oral acyclovir to suppress CMV viruria or induce
       ganciclovir-resistant CMV in EV antibody positive patients.
       Journal of Acquired Immunodeficiency Syndromes and Human
       Retrovirology 995;8(3):289-291.

	III	NUTRITION

       A. Lessons from monkeys with AIDS

       * BACKGROUND AND STUDY DETAILS

       When some monkeys are infected with SIV (simian
immunodeficiency virus) they develop symptoms similar to humans
infected with HIV. Researchers in the USA have been performing
experiments on monkeys to try and understand some of the intestinal
problems that could happen to HIV-infected humans. Before infecting
monkeys with SIV, researchers made sure that they were healthy and
did not have any infections. Technicians infected 9 female monkeys
with SIV and kept 3 uninfected monkeys for comparison.

       * RESULTS

       The researchers killed 3 monkeys within a month after
infecting them. Another 4 monkeys were killed when they developed
AIDS. The monkeys developed:

       - severe diarrhea
       - weight loss
       - persistently swollen spleens and lymph nodes/tissues
       - liver damage
       - low levels of red blood cells
       - various infections

       * LOOKING FOR NUTRIENTS

       Technicians tested blood samples from the monkeys both before
and after SIV infection to measure the level of nutrients-vitamins,
minerals, protein and lipids. Compared to values before SIV
infection most monkeys had lower-than-normal levels of

       - zinc
       - vitamin A
       - vitamin B-l2
       - vitamin E
       - protein

       These monkeys developed nutrient deficiencies when they
developed AIDS. The exception was zinc where the monkeys became
deficient long before AIDS developed. These decreases in nutrient
levels were statistically significant.

       * LIPIDS

       SIV-infected monkeys developed high blood levels of
triglycerides (fat). This increase in triglycerides was
statistically significant. That there was an increase in
triglycerides was not surprising; HIV-infected humans have a similar
change. High blood levels of triglycerides may mean that the monkeys
were producing high levels of interferon-alpha.

       * DAMAGE

       The researchers fond that SIV-infected monkeys had damaged
intestines, perhaps due to SIV or other microbes. As a result of
this damage it is likely that their intestines did not absorb
nutrients as they normally would, so it is not surprising that the
animals developed nutrient deficiencies despite getting an adequate
diet. This data from well-fed SIV-infected monkeys clearly show that
nutrient deficiencies happen. It is likely that HIV infection causes
similar problems in HIV-infected humans.

       REFERENCES:

              1. Stone JD, Heise CC, Miller CJ, et al. Development
       of malabsorption and nutritional complications in Simian
       Immunodeficiency Virus-infected rhesus macaques. AIDS
       1994;8(9):1245-1256.

       B. The importance of Vitamin E

       * FREE RADICALS

       Free radicals are highly active molecules produced by
chemical reactions. Cells of the immune system can release a burst
of free radicals at invading microbes when defending the body.
Uncontrolled and continuous production of free radicals can damage
cells and their contents. To protect itself from the damage of free
radicals the body can use vitamins C and E, and beta carotene which
it absorbs from food. Using the minerals copper, manganese, selenium
and zinc the body can make its own antioxidant enzymes.

       * FREE RADICALS AND HIV

       Some researchers have found that the antioxidant defense
system weakens over time in patients with HIV/AIDS. Why that happens
is not clear but HIV infection may place an extra demand on the body
for antioxidants. Damage to the intestine (by HIV or other microbes)
may reduce the amount of nutrients the body can absorb which in turn
reduces the body's ability to make antioxidants. Frequent infections
and loss of appetite/poor eating habits may also play a role. Drugs
used to treat the infections seen in AIDS may themselves be toxic
and this places an additional demand for antioxidants as the body
attempts to reduce the toxicity of these drugs. Thus it seems that
patients with HIV/AIDS may need extra antioxidants and substances
with which to make antioxidant enzymes (trace minerals, sulphur-
containing amino acids methionine and cysteine). Supplements of
vitamin E may be useful.

       * VITAMIN E--MORE THAN JUST AN ANTIOXIDANT

       Results from experiments indicate that vitamin E is an
important nutrient and helps maintain the health of humans and
animals. This vitamin may have anti-cancer activity in some
experiments. Researchers are still trying to understand the
relationship between  vitamin E and cancer. This vitamin is also
important for nerve cells and other parts of the body.

       * SOURCES OF VITAMIN E

       Vitamin E can be found in safflower and sunflower
seeds. Other good sources of that vitamin include wheat
germ and whole grains. In general, food from animals
is not a good source of vitamin E. The vitamin dissolves
in fat and people whose intestines are inflamed or who have problems
absorbing fat may not get enough vitamin E. The recommended daily
allowance for adult males is 10 mg/day and for non-pregnant females
it is 8 mg/day. Pregnant women are supposed to take 10 mg/day.

       * VITAMIN E AND THE IMMUNE SYSTEM

       Results from laboratory experiments with cells show that
vitamin E is "essential for the normal functioning of the immune
system." In experiments on premature infants with a deficiency of
vitamin E, a dose of 400 International Units boosted the functioning
of their immune system. This effect happened in infants with a
deficiency of GSH (glutathione) which is an important molecule the
body uses to make antioxidant enzymes. Interestingly, deficiencies
of GSH happen in HIV- infected humans. Vitamin E treated cells
reduce production of the immunosuppressive chemical PGE2.

       * CELL_MEDIATED IMMUNITY (CMI)

       In HIV-infected humans the ability of the immune system to
control certain infections decreases with time. Microbes that can
infect and 'hide' inside cells cause many of the life-threatening
infections seen in AIDS. These infections occur because the immune
response needed (CMI) is weak. Vitamin E appears to boost CMI (in
non-HIV-infected subjects). Indeed, in one experiment 800 IU/day of
vitamin E for 1 month enhanced DTH (delayed-type hypersensitivity)
responses that are the hallmark of CMI. Healthy elderly humans often
have reduced CMI and high doses of vitamin E can restore that type
of response.

       * PROTECTING LIPIDS WITH VITAMIN E

       People eating diets high in PUFAs (poly unsaturated fatty
acids including those found in corn/soy oil) may need extra vitamin
E. PUFAs can be damaged by free radicals and these damaged or
oxidized lipids then become immunosuppressive. Indeed, researcher
Chester Myers 'comments that people with HIV/AIDS should minimize
their intake of corn, soy, safflower and sunflower oils.' Some
people may also be taking supplements of borage oil, fish oil (with
vitamins A and D removed), evening primrose or flax seed oils. These
oils may become damaged or oxidized and also become immuno-
suppressive so extra vitamin E and beta carotene may be needed to
protect them.

       * DOSAGE

       As a general rule, patients with HIV tend to have decreasing
levels of nutrients over time if they do not take supplements. For
doctors considering doses,  researcher Chester Myers suggests, "in
general, in [healthy, symptom-free humans without intestinal
problems that reduce absorption] supplementation with 800 IU/day of
vitamin E could be considered as an upper safe level to achieve [an
optimal] cell-mediated immune response....in the presence of HIV
[infection] it would seem that this be considered a reasonable level
of supplementation in general, and that the 'upper level' could be
increased somewhat, probably to 1600 IU/day."

       This does not apply to patients who have problems with
getting their blood to clot or who may be using anti-clotting drugs.
Further information on these type of patients appears in the section
on toxicity later in this issue.

       REFERENCES:

              1. Meydani M. Vitamin E. Lancet 1995;345:170-175.

              2. Beach RS, Mantero-Atienza E, Shor-Posner G, et al.
       Specific nutrient abnormalities in asymptomatic HIV-1
       infection. AIDS 1992;6:701-708.

              3. Myers CD. Use of vitamin E by people living with
       HIV. Written communication. 29 March, 1995.

              4. Council on scientific affairs. Vitamin preparations
       as dietary supplements and therapeutic agents. Journal of
       American Medical Association 1987;257:1929-1936.

              5. Bendich A. Antioxidant vitamins and their function
       in immune responses, pages 35-55 in: Antioxidant nutrients and
       immune function, ed. Bendich A, Phillips M, Tengerdy RP.
       Plenum Press,  New York, 1990.

              6. Bukrinsky MJ, Nottet HSLM, Schmidtmayerova H, et
       al. Regulation of nitric oxide synthesase activity in Human
       Immunodeficiency Virus Type I (HIV-I)-infected monocytes:
       implications for HIV-associated neurological diseases.
       Journal of Experimental Medicine 1995;181:735-745.

       IV TOXICITY

       A. The safety of vitamin E

       * BACKGROUND

       Researchers in England and the USA have recently reviewed
results from clinical trials of vitamin E (in non-HIV-infected humans
and animals) and we present their results below.

       * ANIMAL EXPERIMENTS

       Vitamin E protects cells and lipids from damage by highly
active molecules called free radicals. Although a minimum daily dose
of 30 mg vitamin E may be recommended, some doctors and researchers
"recommend significantly larger doses." Vitamin E does not appear to
cause cancer, mutations or damage the fetus in experiments on rats.
Very high doses of vitamin E can increase the time blood takes to
clot. The body needs vitamin K to help blood clot. Animals with a
deficiency of vitamin K given high doses of vitamin E may have their
ability to clot blood impaired.

       * HUMAN STUDIES

       Although a number of studies on humans suggest that high
doses of vitamin E may have caused side effects, we will confine our
report to data from trials where one group of subjects received
vitamin E and another, similar group of subjects did not. In some
cases, neither doctors nor subjects knew who was receiving vitamin
E. Indeed, many of the side effects supposedly caused by vitamin E
"could, in most cases, not be [found] in controlled studies."

       * CONTROLLED STUDIES

       "In 6 controlled double-blind studies with placebo in which
doses of 600 and 3,200 mg vitamin E were taken daily for 3 weeks to
6 months, few specific side effects were observed." In one study
healthy adult subjects received either oral vitamin E 600 IU/day or
placebo for 4 weeks. Effects NOT detected included:

       - improved physical performance
       - improved general well-being
       - muscle weakness
       - indigestion
       - prolonged time for blood to clot
       - decreases in certain white blood cells (leucocytes)

       Side effects detected were:

       - slightly higher blood levels of cholesterol
       - lowered blood levels of thyroid hormones (T3 and T4) in
         men, and in women who were not taking oral contraceptives.

       Researchers involved with another study of 30 "healthy adults
[who] received 800 IU/day or placebo" for 16 weeks did not find any
different side effects between subjects receiving vitamin E or
placebo.

       * CONTROLLED STUDIES--DOSE AND ABSORPTION

       In one experiment "14 healthy male college students took
vitamin E 900 IU/day and 5 others a placebo for 3 months. Again,
vitamin E did not cause side effects. Data from this study are
interesting because researchers measured vitamin E levels in blood
cells. The build up of vitamin E occurred in "blood, blood cells and
tissue cells." The amount of vitamin E reached its highest level
after "4 weeks." Despite continued intake of vitamin E its
concentration did not increase. Technicians did not find changes in
blood levels of thyroid hormones, liver enzymes, cholesterol or the
time needed for blood to clot. Another study using 1,600 IU/day in
adults did not find "significant side effects."

       * CONTROLLED STUDIES IN UNHEALTHY SUBJECTS

       One controlled study used subjects with "diabetes or coronary
heart disease": given 2,000 IU/day for 2 and then later 6 weeks.
Researchers found that weakness, fatigue and bleeding did not occur
in a greater incidence in these subjects.

       * VERY LARGE STUDIES AND DOSES

       One reviewer examined results on "over 9,000 [subjects] who
had taken up to 3,000 IU/day vitamin E over a period of 11 years."
Researchers did not detect significant side effects.

       * FOCUS ON BLEEDING AND VITAMIN K

       In healthy subjects high doses of vitamin E can increase the
time blood needs to clot. Deficiencies of vitamin K happen in
patients with problems absorbing nutrients from their intestines.
Vitamin K is produced by friendly bacteria living in the intestine.
In a study with 6 subjects given "100 or 400 IU/day vitamin E" who
took drugs to lengthen the clotting time of their blood, vitamin E
did not appear to lengthen the time for bleeding to stop. In a study
on older, sicker subjects taking 2 anti- clotting drugs, 1,200
IU/day of vitamin E caused clotting problems which stopped when they
stopped taking vitamin E. In 19 subjects with cystic fibrosis (a
condition where the intestines are inflamed and malabsorption
occurs) subjects given 100 to 200 IU/day vitamin E developed
clotting problems. Overall, researchers concluded that vitamin E by
itself did not affect blood clotting. In humans with vitamin K
deficiency and/or intestinal malabsorption and/or taking
anti-clotting drugs, high doses of vitamin E may cause the clotting
time to increase. Obviously, hemophiliacs and others with impaired
blood clotting should seek medical advice and supervision when
considering supplementation with vitamin E.

       * BLEEDING: NEWS FROM 1 SUBJECT

       We know of 1 HIV-infected patient (without haemophilia) who
notices that whenever he takes more than 1,000 IU/day of vitamin E,
small cuts from shaving can take up to 10 minutes to stop bleeding.
Readers should note that this patient also takes supplements of
Aspirins and fish oil on a regular basis, these drugs lengthen the
time blood needs to clot.

       The reviewers concluded that doses between 100 and 300 IU/day
appear to be safe in adults. Doctors elsewhere may recommend higher
doses of vitamin E for their patients with infections, and liver
damage (from alcohol) as well as those receiving frequent exposure
to X-rays. Further information on dosage appears in the section on
nutrition and vitamin E.

       ACKNOWLEDGEMENTS:

       We thank Chester Myers for helpful comments, reviews and
support.

       REFERENCES:

              1. Kappus H and Diplock AT. Tolerance and safety of
       vitamin E: a toxicological position report. Free Radical
       Biology and Medicine 1992;13:55-74.

              2. Umegaki K and Ichikawa T. Decrease in vitamin E
       levels in the bone marrow of mice receiving whole-body X-ray
       irradiation. Free Radical Biology and Medicine 1994;17(5):439

              3. Meydani SN, Meydani M, Rall LC et al. Assessment of
       the safety of high-dose, short-term supplementation with
       vitamin E in healthy older adults. American Journal of
       Clinical Nutrition 1994;60:704-809.


       V CANCER

       A. Interferon-alpha and antibodies for lymphoma?

       * BACKGROUND

       Perhaps because antibody-producing B cells seem
overstimulated, patients with HIV/AIDS can develop cancers from B
cells more so than from T cells. Anti- cancer drugs can cause
bone-marrow damage, weakening the patient and reducing quality of
life while not usually providing a cure. Thus doctors and their
patients are looking for innovative and less toxic treatments.
Researchers in Denmark have been experimenting with an unusual
therapy for HIV-related lymphoma.

       * STUDY DETAILS

       The researchers enrolled 5 male subjects with B cell lymphoma
into their study. Two subjects had 20 CD4+ cells and three others
had at least 250 CD4+ cells. Researchers gave subjects 3 million
IU/day of interferon-alpha injected into muscles for 1 week. The
interferon used was Intron-A(R) made by Schering-Plough. After that
subjects received interferon-alpha 3 times per week and infusions of
antibodies in a dose of 400mg/kilogram of body weight (gamma
globulin or Gammaguard(R) made by Baxter) "every 2 weeks for 6
months."

       * RESULTS

       In 1 subject all his tumours disappeared but then 3 months
later new ones appeared. In two others the tumours continued to
spread, while in the remaining 2 subjects the tumours shrank but did
not disappear. The researchers noted that subjects in this study
seemed to have survived longer than most subjects with HIV- related
lymphoma. They cite a figure between 4 and 7 months being typical
for this problem in AIDS. Two of the subjects continued to live 14
and 19 months after receiving treatment. The researchers think that
a larger study needs to be done to investigate this unusual
anti-cancer therapy to confirm their results and understand how it
works.

       REFERENCES:

              1. Bergmann OJ, Madsen M, Kristensen JS, et al.
       Treatment of AIDS-associated lymphoma with interferon-a and
       intravenous gamma globulin. AIDS 1995;9(3):305-306.

              2. Fust G, Dierich MP and Hidvegi T. Role of humoral
       factors in the progression of HIV disease. Immunology Today
       1995;16(4):167-169.

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