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. Copyright (c) CATIE. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+