TreatmentUpdate 55 - Vol. 7, No. 1 - January 1995 ************************************************* Published by Community AIDS Treatment Information Exchange, Suite 420-517 College Street, Toronto, Ontario, Canada M6G 4A2. ************************************************* I HIV/AIDS THEORY A. HIV and cytokines * BACKGROUND Cytokines are chemicals (such as the interferons and interleukins) that are made by the immune system. The immune system releases certain cytokines to help recruit cells and manage the fight against infections. Once the infection is cured other cytokines are released which help to 'turn off' the response against the infection. * TWO TYPES OF RESPONSES There are two types of responses the immune system can make when it senses an infection. One response is called CMI (cell-mediated immunity, also known as a type 1 response). Very simply, CMI involves T cells that fight invading microbes and destroy infected cells. To boost CMI the immune system makes cytokines such as: - interferon-gamma - interleukin-2 - interleukin-12 As a general rule, CMI is needed to fight infections caused by viruses and other microbes that can infect and 'hide' inside cells. The other type of response is called humoral immunity or type 2. Here the immune system relies on antibodies made by B-cells. To strengthen this response the immune system releases cytokines such as: - interleukin-4 (IL-4) - IL-6 - IL-10 Interestingly, these cytokines cause cells to make less of the cytokines needed for CMI. As well, interferon-gamma can cause cells to decrease production of the cytokines needed for humoral immunity. * HIV As a result of new discoveries on the cutting edge of immunology, researchers have began to form a more sophisticated model of HIV infection. When the immune system first detects HIV it can make a response based largely on antibodies or it may try and contain the infection using T cells. Those people whose immune systems make the antibodies become "HIV-positive". Despite making large amounts of antibodies, most patients eventually develop AIDS. Several research teams have found people who have been exposed to HIV, yet did not make antibodies. Instead, their immune systems appeared to contain and manage the infection using T cells. Some researchers suggest that, over time, those HIV-antibody positive patients make less of the chemicals that can boost CMI while making more of the chemicals that help humoral immunity. This shift in cytokine balance favouring humoral immunity may also be why patients with HIV/AIDS become allergic to drugs. As CMI weakens, life- threatening infections appear. Eventually, humoral immunity also weakens. * EARLY WARNING Based on results of experiments with cells and HIV, it appears that HIV-infected immune systems become less able to detect invading microbes. Moreover, even when T cells are given a 'description' of the microbe(s) they are supposed to attack, their attempts are weak and the infection is not always contained. In much of the basic research on HIV it is clear that CD8+ cells are important in helping fight off many of the infections seen in AIDS. These cells also play a role in managing the immune system and should not be thought of as simple 'suppressor' cells. In the next report we present findings on cytokine therapy. ACKNOWLEDGEMENTS: 1. Thanks to B. Goldberg for helpful discussions, access to research papers and researchers. REFERENCES: 1. Mossmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone: definition according to profile of lymphokine activities and secreted proteins. Journal of Immunology 1986;136(7):2348-2357. 2. Mossmann TR. Cytokine patterns during progression to AIDS. Science 1994;265:193-194. 3. Clerici M and Shearer G. The Th1-Th2 hypothesis of HIV infection: new insights. Immunology Today 1994;15(12):575-581. 4. Rowland-Jones S, Sutton S, Ariyoshi K, et al. HIV-specific cytotoxic T cells in HIV-exposed but uninfected Gambian women. Nature Medicine 1995;1(1):59-64. 5. Meyaard B, Otto SA, Keet IPM, et al. Changes in cytokine patterns of CD4+ T cell clones in Human Immunodeficiency Virus infection. Blood 1994;84(12):4262-4268. 6. Maggi E, Giudizi MG, Biagiotti R, et al. Th2-like CD8t cells showing B cell helper function and reduced cytolytic activity in Human Immunodeficiency Virus type-1 infection. Journal of Experimental Medicine 1994;180:489-495. 7. Paganlli R, Scala E, Ansotegui LJ, et al. CD8+ T lymphocytes provide helper activity for IgE synthesis in Human Immunodeficiency Virus-infected patients with hyper-IgE. Journal of Experimental Medicine 1995;181:423-428. 8. Seder RA and Le Gros GG. The functional role of CD8+ T helper type 2 cells. Journal of Experimental Medicine 1995;181:5-7. 9. Quill H, Bhandoola A, Trinchieri G, et al. Induction of ILr12 responsiveness is impaired in anergic T lymphocytes. Journal of Experimental Medicine 1994;179:1065-1070. B. Testing the theory * BACKGROUND Several research teams have noted a decrease in cell- mediated (CMI) immunity in EGV-infected patients as their CD4+ cell counts fall over time. As well, production of cytokines associated with CMI (interferon-gamma, IL-2 and IL-12) fall in HIV/AIDS while production of cytokines associated with humoral immunity (IL-4, 6, 10) rise. Thus some researchers are suggesting giving subjects with HIV/AIDS extra cytokines that may boost CMI. But the immune systems of such patients are complex and may not necessarily be quickly repaired when they receive supplements of cytokines. * 27 YEARS OF RESEARCH One prominent American researcher said that scientists have been studying cytokines for over 27 years and apart from the bone marrow stimulants GM-CSF and EPO, cytokine therapy has not been "terribly successful". This is because cytokines: - quickly break down - are needed at very small and particular sites - can be toxic when taken in large doses Some researchers are beginning to suspect that there will not be any single 'magic' cytokine for treating HIV/AIDS. Leading immunologists suspect this is the case because there is usually a 'mix' of cytokines that cause certain effects. * ANTI-CYTOKINES? Some doctors think about using cytokines in a "positive" way; that is, giving patients extra cytokines such as IL-2 and interferons. But in lab experiments, adding extra interferon-gamma did not reduce the effect of IL-4 or IL-10, but using anti-IL-4 antibodies did. In mice infected with a virus that gives them AIDS, anti-IL-4 antibodies delayed the development of AIDS. * TESTING THE THEORY - CANCER In the section on cancer in this issue of TreatmentUpdate researchers found that anti-IL-6 therapy had weak anti-cancer effects. Their next attempt may include attacking IL-6 and other cytokines, such as IL-10 with chemotherapy. * TESTING THE THEORY - ARTHRITIS Researchers in the European Union have used an antibody that attacked the cytokine TNF-alpha (tumor necrosis factor). Subjects in that study received a placebo or the anti-cytokine called cA2. Short-term use of this product improved subjects' quality of life but did not cure their disease. * MAKING A BLOCKADE In order for a cytokine to interact with a cell, the cell usually has a receptor to which the cytokine binds (much like a key fitting into and opening a lock). Some researchers suggest that receptor blockers or receptor antagonists should be used to block the effect of certain cytokines on cells. The problem here is that when the receptor for the cytokine gets blocked the body continues to produce high levels of the cytokine. Clearly a more sophisticated approach needs to be developed. Part of the problem is that researchers don't know how to produce the right mix of cytokines or anti-cytokines that can boost CMI. Without this information some HIV-infected patients and their doctors may resort to using products such as: - DNCB (TreatmentUpdate 43 and 55) - Imreg-1 (TreatmentUpdate 24 and 29) - papaverine (TreatmentUpdate 46 and 48) - Salk HIV vaccine or Immunogen that may cause the (delayed-type hypersensitivity) skin reactions that are the sign of cell-mediated immunity. Preliminary results from the Salk HIV vaccine trials will appear in a future issue of TreatmentUpdate. REFERENCES: 1. Barcellini W, Rizzardi GP. Borghi MO, et al. Th1 and Th2 cytokine production by peripheral blood mononuclear cells from HIV-infected patients. AIDS 1994;8(6):757-762. 2. Bloom B. The power of negative thinking. Journal of Clinical Investigation 1993;91:1265-1266. 3. de Hon FD, Ehlers M, Rose-John S, et al. Development of an interleukin (IL) 6 receptor antagonist that inhibits IL-6-dependent growth of human myeloma cells. Journal of Experimental Medicine 1994;180:2395-2400. 4. Kanagawa O, Vaupel BA, Gayama S, et al. Resistance of mice deficient in IL 4 retrovirus-induced Immunodeficiency Syndrome (MAIDS). Science 1993;262:240-242. 5. Debets R and Savelkoul HFJ. Cytokine antagonists and their potential therapeutic use. Immunology Today 1994;15(10):455458. 6. Elliot MJ, Maini RN, Feldmann MF, et al. Randomized, double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344:1105-1110. II IMMUNOMODULATORS A. HIV and the kidney * BACKGROUND In the early 1980s researchers found that some patients with HIV/AIDS had damaged kidneys. This complication even appeared in symptom-free patients. In the USA, HIV-infected patients from Miami and New York were more likely to have kidney dysfunction than patients from rural areas. In some patients the kidneys remove protein from the blood and dump it into the urine. Over the long term, this loss of protein and continued kidney damage may be dangerous. Researchers in Germany have been studying HIV- related kidney problems to try and find out why they happen. For their study the researchers recruited 90 subjects. * STUDY DETAILS All subjects were adults and had CD4+ cell counts greater than 500 cells. As well, all subjects received AZT 500 mg/day. Technicians performed ultrasound and other tests. * RESULTS: DRUG USERS AND MEN WHO HAVE SEX WITH MEN Looking at ultrasound scans, the researchers could not find any severe damage to the kidney. About 11 subjects had relatively high levels of protein in their urine. Gay/bisexual men and subjects with less than 200 CD4+ cells seemed more likely to have high levels of protein in their urine. Among the gay/bisexual men who had high levels of protein loss, 2 had CMV (cytomegalovirus) infection. When doctors gave these subjects the anti-CMV drug ganciclovir (DHPG, Cytovene(R)) protein loss dropped dramatically. Among drug users, high protein loss in the urine happened at CD4+ cell counts above 200 cells. One drug user had high blood levels of antibodies against the parasite that causes toxo (toxoplasmosis) Another drug user with a chronic chlamydia infection also had high levels of protein in his urine. In this study the researchers divided the subjects into 4 groups based on how they became infected with HIV; hemophiliacs, heterosexual/transfusion recipients, gay/bisexual men and injection drug users. Some gay/bisexual men seemed more likely to have high levels of protein in their urine. This was still the case when the researchers looked at the other subjects with similar CD4+ cell counts. According to the researchers, there may be several reasons for protein loss and kidney damage: - kidney malfunction - immune complexes being dumped in the kidney (irnmune complexes are a combination of an antibody joined to a protein, in this case, to HIV) - heroin toxicity - other infections The researchers warn that patients with high levels of protein in their urine may be at risk for kidney damage from acyclovir (Zovirax) and certain antibiotics such as aminoglycosides (including gentamycin, neomycin and streptomycin). REFERENCES: 1 . Busch HW, Riechrnann ST, Heyen P, et al. Albuminuria in HIV- infected patients. AIDS Researeh and Human Retrovuuses 1994;10(6):717-720. B. Corticosteroids for the kidney? * FOUR SUBJECTS Doctors in Cleveland, Ohio, have recently reported their results in treating 4 HIV-infected patients with kidney dysfunction. All subjects were adults, 2 males and 2 females. Three of these subjects had used AZT and one, ddI. The CD4+ cell counts ranged from 30 to 80 cells. Doctors treated them with the corticosteroid Prednisone 60 mg/day "for 2 to 6 weeks." All subjects improved and protein loss was reduced. The doctors suggested that short-term use of steroids "does not substantially increase the risk of life-threatening infections." Two subjects developed MAC infections, but when the doctors stopped giving the subjects steroids the patients survived the infection. Other doctors may wish to consider testing concentrated fish oil (with the vitamins A and D removed) or flax seed oil (with beta- carotene and vitamin E used as preservatives) as potential anti-inflammatory kidney treatment. REFERENCES: 1. Smith MC, Pawar R, Carey JT, et al. Effect of corticosteriod therapy on human Immunodeficiency virus-associated nephropathy. American Journal of Medicine 1994;97:145-151. 2. Donadio JV, Bergstralh EJ, Offord KP, et al. A controlled trial of fish oil in IgA nephropathy. New England Journal of Medicine 1994;331(18):1 194-1 199. C. DNCB-long-term results * STUDY DETAILS For background information on DNCB please see TreatmentUpdate 43. We now report results from a long term observational study on DNCB. Researchers in California enrolled 24 male, HIV-infected subjects for this study; - 18 subjects "had no symptoms" - 6 had persistently swollen lymph nodes - the average CD4+ cell count was 346 cells (ranging between 170 and 560 cells) Subjects used a 'Q-tip' to dip into a 10% solution of DNCB which they then 'painted' on to a "2 inch square of skin" to see if they had been exposed to DNCB in the past. A month after first applying the 10% solution subjects began to use a 2% solution on a 2-inch square of their skin. If subjects then had a strong reaction-redness, itching-they used the weakest strength of DNCB that could cause a reaction on their skin. * STOPPING USE OF THE DRUG Eventually researchers found that 13 subjects continued to use DNCB on a regular basis while another 11 did not. Those subjects who stopped using DNCB did so after about 11 months. On average, researchers monitored subjects for over 2 years; some subjects were observed for almost 4 years. Two subjects also used a combination of AZT and ddC, two others AZT and ddI and seven others used AZT alone. Three subjects who used DNCB on a regular basis also took AZT. * TOXICITY AND OTHER EFFECTS Three subjects had side effects. The first had a rash over most of his body when he exercised right after his first DNCB patch. His reaction cleared in two hours. The other 2 subjects had very red and irritated reactions on the skin where they put a 10% solution of DNCB. Within 48 hours these reactions cleared. The study's researchers suggest that DNCB use appears to be "safe" in this small group of subjects. Three subjects noted that they had "significant" increases (no precise data provided) in their weight while using DNCB. According to the researchers, the weight gain did not appear to be caused by other drugs. * SYMPTOMSOF HIV/AIDS According to the researchers those subjects who stopped using DNCB after 11 months "appeared [more likely to develop] AIDS". None of these subjects stopped using DNCB because they became ill. * CD4+CELLS Both regular users of DNCB (who had 396 cells at the start of the study and 211 cells at the end) and non-users (who had 315 cells at the start of the study and 122 cells at the end) had decreased CD4+ cell counts. This difference between the 2 groups, with the DNCB users having a less severe decline, was statistically significant. The different CD4+ counts between the 2 groups at the start of the trial were not statistically significant. * CD8+AND OTHER CELLS Subjects who used DNCB on a regular basis had slightly increased levels of CD8+ (from 1014 to 1093 cells) and NK (natural killer) cells compared to subjects who did not take the drug on a regular basis (from 1234 to 920 cells). This difference between the 2 groups was statistically significant. At least 2 studies in the USA suggest that having a high CD8+cell count may mean that such subjects are less likely to die than subjects with less than 400 CD8+ cells. Researchers did not carry out any performance tests on CD8+ and NK cells taken from users of the drug. DNCB also appeared to increase certain types of CD8+ cells in users, but researchers are not sure just what this means. * INFECTIONS/DEATHS Researchers found that 2 of 13 subjects using DNCB on a regular basis developed skin lesions of KS (Kaposi's sarcoma). In one subject the lesion faded, in the other no new lesions appeared. No subject who continued to use the drug died. Five of 11 subjects who stopped using the drug developed AIDS; 3 had the life- threatening lung infection PCP; 2 had KS. These 5 subjects used DNCB for an average of 9 months and developed AIDS about 10 months after they stopped using the drug. Eventually 4 of the 5 subjects died. The researchers noted that all the subjects who developed ATDS used AZT and/or other anti-HIV drugs. This does not necessarily mean that AZT and related drugs may have been a factor in their deaths. These subjects may have been sicker at the start of the study and may have had a higher chance of dying than other subjects. Clearly larger and controlled studies of DNCB are needed to find out more about this drug's effects. REFERENCES: 1. Stricker RB, Elswood BF, Goldberg B, et aL CEnical and immunologic evaluation of HIV-infected patients treated with dinitrochlorobenzene. Journal of the American Academy of Dermatology 1994;31(3)part 1:462-466 2. Giorgi JV, Ho HN, Huji K, et al. CD8+ lymphocyte activation of Human Immunodeficiency Virus seroconversion: development of HLA-DR+ CD38- CD8+ cells is associated with subsequent stable CD4+ levels. Journal of Infectious Diseases 1994;170:775-781. III INFECTION FIGHTERS A. Syphilis * BACKGROUND Infections normally kept under control may reappear as the immune system begins to break down under constant attack by HIV. A number of researchers have claimed that in patients with HIV/AIDS: - lab tests for syphilis may not be accurate - standard anti-syphilis therapy may not be effective - chronic infection with T. pallidum (the cause of syphilis) may weaken the immune system Doctors at a clinic in Baltimore, Maryland, have been studying the interaction between syphilis and HIV. By reviewing records on over 300 patients (both HIV- infected and non-infected) from their clinic they hoped to find information that might be useful when caring for HIV-infected patients who also have syphilis. * STUDY DETAILS The doctors looked at data from patients with primary or secondary syphilis or early latent syphilis. Patients who had primary syphilis had: - an ulcer on their genitals - detectable T. pallidum in samples from those ulcers - a 'positive' FTA-ABS test (reactive fluorescent treponemal antibody absorption test). Researchers used this test because it gave them more accurate results than the RPR (rapid plasma reagin test card) test. Patients with secondary syphilis had: - rash - mucous patches - wart-like lesions, and a 'positive' RPR/FTA-ABS test in the past 12 months. Prior to this their test result was 'negative'. Patients with early syphilis had: - no symptoms - had a 'positive' RPR/FTA-ABS while in the past 12 months these tests had been 'negative'. * RESULTS The researchers found that HIV+ patients (both men and women) were more likely to have secondary syphilis than early syphilis. There was a trend when the researchers looked at CD4+ cell counts. Subjects with less than 500 CD4+ cells were more likely to have secondary syphilis. All four patients with less than 200 CD4+cells had secondary syphilis. * TREATMENT Patients received either one injection of benzathine penicillin or 200 mg/day of doxycycline for 2 weeks. Despite this treatment 16 subjects did not recover. Interestingly, fifteen of these patients had received the single injection of benzathine penicillin. Eighteen percent of HIV-infected and 14% of the non-HIV- infected did not respond properly when they received treatment. This difference was not statistically significant. REFERENCES: 1. Hutchinson CM, Hook EW, Shepard M, et al. Altered clinical presentation of early syphilis in patients with Human Immunodeficiency Virus infection. Annals of Internal Medicine 1994;121 :94-99. B. Azithromycin for syphilis? * BACKGROUND For treating patients with syphilis, the CDC (Centers for Disease Control and Prevention, Atlanta, Georgia) recommends using the antibiotic penicillin. Penicillin may not work in some patients and others may be allergic to it. Alternatives include ceftriaxone, tetracyclines and erythromycin. The CDC recommends that erythromycin should only be used for early treatment of syphilis where the patient can be monitored for 12 months. Azithromycin is an antibiotic that is 'related' to erythromycin and clarithromycin which some doctors use to treat patients with MAC and 'toxo' (toxoplasmosis). The company that sells azithromycin, Pfizer, has been studying the effect of azithromycin on subjects with primary and secondary syphilis. In previous work azithromycin can block the growth of T. pallidum (the cause of syphilis) and is effective in treating rabbits with syphilis. * STUDY DETAILS All 16 subjects were adults (10 male and 6 female) and the doctors recruited them from a clinic that specialized in the treatment of sexually transmitted diseases. Subjects were supposed to take 500 mg/day of azithromycin "for 10 days." Over the next 6 months most subjects returned to the clinic for observation and lab tests. Three subjects did not return for follow-up visits. * RESULTS According to the researchers, 11 subjects were "cured". The doctors based their diagnosis on the results of blood tests. As well, subjects who recovered usually had their symptoms (such as sores on their genitals, swollen lymph nodes and rash) clear. Two other subjects were not cured; either they never recovered or were re-infected. * TOXICITY Five subjects had some side effects including nausea, vomiting, "mild cramps, loose stools or diarrhea." Subjects described these symptoms as "mild" except for the one subject who vomited. No toxicity to the bone marrow, liver or kidney was detected. * HIV It is not clear what will happen to other patients with both HIV and syphilis who are treated with azithromycin. Some researchers note that there is a complex interplay between T. pallidum and the irnmune system. As well, diagnostic technology for syphilis generally seems not to have advanced the way tests for some other diseases have. Perhaps better tests may make clear what happens when HIV+ patients become infected with T. pallidum. REFERENCES: 1. Verdon MS, Handsfield HH and Johnson RB. Pilot study of azithromycin for primary and secondary syphilis. Journal of Infectious Diseases 1994;19:486-488. 2. Fitzgerald TJ. The Th1/Th2-like switch in syphilitic infection: is it detrimental? Infection and Immunity 1992;60(9):3475- 3479. 3. Riley BS, Oppenheier-Marks, Rodolf JD and Norgard MU. Virulent treponema pallidum promotes adhesion of leucocytes to human vascular endothelial cells. Infection and Immunity 1994;62(10):4621-4625. C. Syphilis in the brain * SYMPTOMS Researchers in Atlanta studied the effect of standard treatment for neurosyphilis in 11 HIV-infected subjects (9 male, 2 female). The subjects were all adults and tested 'positive' for syphilis on standard tests (listed in section A). Medical staff performed a spinal tap to get a sample of CSF (cerebrospinal spinal fluid; in which the brain and spinal cord float). Technicians tested the CSF samples for the microbe that causes syphilis as well as antibodies that suggest syphilis. Subjects had the following signs/symptorns of neurosyphilis: - eye inflammation - swollen/damaged retina - stroke - life-threatening brain infection - "behavioural changes" (the researchers did not provide details about this symptom) Some subjects also had other symptoms-rashes on the hands and feet. Three subjects also had lost hair on parts of their bodies. About half the subjects had a CD4+ cell count of 344 cells. Doctors gave subjects intravenous penicillin G, 18 million to 24 million units daily for 10 days. * REACTIONS TO TREATMENT Six weeks after receiving treatment technicians analysed blood and CSF samples. Using one test called VDRL, it appeared that 7 of 11 subjects recovered from their infection. In 2 of the 4 remaining subjects, it appeared that the infection was not getting worse while in 2 others the infection seemed to get worse. The doctors suggested that the immune systems of these 4 subjects could not contain the infection. * SIX MONTHS LATER Eventually, it appeared that 4 subjects recovered. In 6 subjects analysis of CSF sarnples revealed high levels of white blood cells-suggesting continued infection. Three of these subjects who received additional treatment continued to have high levels of white blood cells in their CSF. Overall, 10 of the 11 subjects had their signs/symptoms of neurosyphilis clear. One subject had symptoms of neurosyphilis (including blindness) that became worse despite aggressive treatment (24 million units/day of penicillin for 2 weeks). By the sixth month she developed more symptoms such as headaches and she had difficulty controlling muscles on the right side of her body. Doctors gave her another 2 week course of "high-dose" penicillin but she "died 2 months later." * WHAT TO DO? High levels of white blood cells in the CSF samples from these HIV-infected subjects suggested that T. pallidum infection continued. Doctors are not sure what to do for such patients. Some doctors wait several months to see if the level of white blood cells in the CSF falls. It may take between 6 and 12 months for this to happen. Using PCR (polymerase chain reaction), technicians found T. pallidum in only 3 of 11 subjects before they received antibiotic therapy. But this probably means that PCR is not "sensitive" enough because all subjects had signs/symptoms of neurosyphilis. Despite increasing the dose of penicillin, T. pallidum infection seemed to get out of control suggesting that this microbe is resistant to penicillin. It is not always clear which patients will recover. Indeed, 3 of the subjects in this trial whose infection became worse did not have the "lowest" CD4+ cell counts. The doctors in this study state that other anti- syphilis therapies need to be tested. As well, because of the difficulty in predicting who will recover from neurosyphilis, the doctors also state that patients with neurosyphilis need "intensive evaluation...including CSF examination, and very careful follow up." REFERENCES: 1. Gordon SM, Eaton ME, George R, et al. The response of symptomatic neurosyphilis to higidose intravenous penicillin G in patients with Human Immunodeficiency Virus infection. New England Journal of Medicine 1994;331(22):1469-1473. IV CANCER A. Cytokines and cancer * BACKGROUND Researchers in the EU and USA have noted that some patients with certain cancers have T cells that do not function properly. In one study of cancer (Hodgkins disease using non-HIV-infected subjects) researchers found that subjects with the weakest T cell response usually had the most severe complications of cancer. In such patients, cell-mediated immunity was poor. These researchers have also documented a similar trend in patients with HIV/AIDS. According to the researchers' theory, as the immune system breaks down, more chemicals are released that weaken CMI. Such chemicals include the cytokines: - 4 (interleukin 4) - IL-6 - IL-10 These chemicals reduce the production of IL-2 and interferon-garnma and favour the growth of more B cells. Perhaps under this chemical stimulation and infection with herpes viruses it is not surprising that B cell cancers occur in AIDS. Treatment of these cancers consists of a combination of anti-cancer drugs- chemotherapy. These drugs are not always effective. Some researchers in France think that by giving patients with AIDS-related cancer anti-cytokines, their quality of life and perhaps survival may be improved, compared with similar patients not given these drugs. REFERENCES: 1. Clerici M and Shearer G. The Thl-Th2 hypothesis of HIV infection: new insights. Immunology Today 1994;15(12):575- 581. 2. Benjamin D, Knobloch TJ and Dayton MA. Human B-cell interleukin-10: B-cell lines derived from patients with Acquired Immunodeficiency Syndrome and Burkitt's lmphoma constitutively secrete large quantities of IL-10. Blood 1992;80(5):1289. B. Lymphoma: BE-8 may improve quality of life * BACKGROUND Researchers in France have created an antibody that attacks the cytokine IL-6 (interleukin 6). Their antibody, called BE-8, was originally made by cells from mice. This antibody had been tested on non-HIV-infected patients with cancer and did not appear to cause any serious toxicity. Our report provides results from a study called ANRS 018. * TYPE OF SUBJECTS Researchers enrolled 11 HIV-infected subjects (9 males, 2 females) with B cell lymphoma in this study. All subjects had less than 40 CD4+cells when they entered the study. Researchers did not release the subjects' CD8+ cell counts. Before entering the study five subjects had received chemotherapy but despite treatment their tumours grew. While receiving infusions of BE-8 subjects did not receive chemotherapy or radiation one month before or during this study. Subjects had tumours in a variety of places including the lung, face, stomach and testicles. * DRUGS AND MONITORING Researchers gave the subjects 125 ml of salt solution which contained BE-8. Technicians took blood samples from subjects to measure a protein called CRP (c-reactive protein). Production of CRP in the liver falls when IL-6 levels decline. As well, doctors also compared the size of tumours before and after subjects received BE-8. At first "3 [subjects received] 10 mg/ day of BE-8." Since CRP levels were still high, the dose of BE-8 was increased to 20 mg/day and up to 40 mg/day if CRP levels did not fall. Subjects were supposed to receive the drug for at least 3 weeks or 1 cycle. Some subjects received the drug for longer periods of time. * RESULTS During the first 21 days of the study about 1/2 the subjects stabilized. Only 4 subjects received BE-8 for more than 21 days. The drug caused CRP levels in the blood to fall and also delayed the growth of the cancer for between 57 and 91 days. * SYMPTOMS Doctors found that 4 subjects with symptoms of lyrnphoma (such as fever and night sweats) had some relief when they received BE-8. Other subjects had increased appetite and weight. Those subjects who received more than 1 cycle of BE-8 continued to gain weight. * SIDE EFFECTS Subjects did not report many side-effects. One subject had headaches "1 hour after" receiving BE-8. No subject had life-threatening infections while in the study. Researchers did allow subjects to use anti-PCP/toxo drugs. All subjects had less than normal levels of platelets (needed for clotting blood) but they did not suffer from prolonged bleeding. Blood levels of white cells called neutrophils fell in subjects but this did not cause any complications. Two subjects rnade antibodies that attacked BE-8 but this did not appear to cause increased growth of the tumours. * SUMMARY While infusions of anti-IL-6 appeared to stop the growth of tumours in some subjects, eventually the tumours continued to grow. BE-8 did affect symptoms of Iymphoma clearing "fever, sweats and [weight loss]". The French research team suggested that combination treatment of AIDS-related Iymphoma with BE-8 and anti-cancer drugs should be tested to see if survival is lengthened. BE-8 may also provide some relief from symptoms for other subjects with cancer. * CYTOKINES AND CANCER Clearly, anti-IL-6 had only weak anti-cancer effects. While researchers have documented changes in the type of cytokines released in patients with HIV/AIDS, trying to use just one type of anti-cytokine is not enough. Effective treatment may require a more sophisticated approach, perhaps blocking the effects of other cytokines such as IL-4 and IL-10. The monoclonal antibody used in this study was made and purified by technicians associated with this trial. REFERENCES: 1. Clerici M, Ferrario E, Trabattoni D, et al. Multiple defects of T helper cell function in newly diagnosed patients with Hodgkins disease. European Journal of Cancer 1994;30A(10):1464-1470. 2. de Hon FD, Ehlers M, Rose-John S, et al. Development of an interleukin (IL) 6 receptor antagonist that inhibits the growth of human myeloma cells. Journal of Experimental Medicine 1994; 180:2395-2400. 3. Emille D, Wijdenes J, Gisselbrecht C, et al. Administration of an anti-interleukin-6 monoclonal antibody to patients with Acquired Immunodeficiency Syndrome and Iymphoma: effect on Iymphoma growth and on B clinical symptoms. Blood 1994;84(8):2472-2479. Copyright (c) 1995 - TreatmentUpdate. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34