TreatmentUpdate59 - Vol 7, No. 5 (May 1995) ----------------------------------------------- Community AIDS Treatment Information Exchange Suite 420 - 517 College Street, Toronto M6G 4A2 (416) 944-1916. ----------------------------------------------- Table of Contents I IMMUNOMODULATORS A. Thalidomide for ulcers B. Low-dose corticosteroids for MAC? II INFECTION FIGHTERS A. Preventing PCP---Bactrim/Septra 3 days a week B. Toxo---standard treatment C. Treating toxo with clarithromycin and minocycline D. Roxithromycin---preventing TB/MAC and toxo? E. Predicting who will get toxo III TOXICITY A. Warning about thalidomide B. Reducing the toxicity of sulpha drugs C. Experiments in France IV TESTING A. Skin tests to predict infections B. Skin tests on HIV-infected and non-infected people. ---------------------------------------------------------- I IMMUNOMODULATORS A. Thalidomide for ulcers * BACKGROUND Some patients with HIV infection develop painful sores and ulcers on the skin, in the mouth and throat, intestines and other parts of the body. In some cases these ulcers may be caused by viruses such as CMV (cytomegalovirus) and HSV (herpes simplex virus). Bacteria and fungi can also cause ulcers. In cases where technicians have found microbes causing the ulcer, treatment with drugs-antibiotics, antifungals or antivirals-can bring some relief. There are cases where the ulcers do not appear to be caused by microbes. In such cases the ulcers may be caused by the immune system attacking parts of the body. Drugs that can 'suppress' the activity of the immune system may provide benefit. Corticosteroids may be helpful and doctors in Australia have recently reported their experience with the tranquilizer thalidomide. * STUDY DETAILS Researchers reviewed hospital records on 20 HIV-infected subjects who had ulcers and who received thalidomide. All of these doctors had prescribed a variety of drugs for treating ulcers on their patients but none worked. All subjects were adult males and most (80%) had less than 200 CD4+ cells. Subjects received thalidomide 200 mg/day for 2 weeks taken at night. In some cases doctors increased the dose of thalidomide to 300 mg/day and in others the dose remained the same but they received thalidomide for 2 months. * RESULTS In 70% of cases the ulcers healed; in others, they became smaller and less painful. Subjects with ulcers in their rectum required prolonged treatment-more than 2 weeks. About 1/3 of subjects developed side effects:  rash-5 subjects  nerve damage (peripheral neuropathy)--1 subject  "excessive [tiredness, low energy]"--1 subject The rash cleared when subjects stopped taking the drug. Others continued using thalidomide despite rash. The nerve damage cleared when the affected subject stopped using thalidomide. About 1% of non-HIV-infected subjects given thalidomide may develop a rash. The subject who felt 'excessive [tiredness and low energy]' stopped using thalidomide (the doctors did not state how long it took him to recover). Giving subjects the drug at night or reducing the dose to 100 mg/day seemed to reduce drowsiness during the day. * THALIDOMIDE AND THE IMMUNE SYSTEM The doctors conducting the study noted that thalidomide did not reduce CD4+ cell counts. Examination of their data revealed that 9 subjects had decreased CD4+ cell counts while 5 had increased CD4+ cell counts. Unfortunately CD4+ cell counts alone do not reveal the complex state the immune system is in when infected with HIV. Information on the effect of thalidomide on the immune system appears in the section on toxicity later in this issue of TreatmentUpdate. REFERENCES: 1. Paterson DL, Georghiou P, Allworth AM and Kemp R. Thalidomide as treatment of refractory aphthous ulceration related to Human Immunodeficiency Virus infection. Clinical Infectious Diseases 1995;20:250-254. B. Low-dose steroids for MAC? * BACKGROUND Infection with MAC (Mycobacterium avium complex) can be a problem for some HIV-infected patients who have less than 75 CD4+ cells. Symptoms can include:  fever  unintentional weight loss  night sweats  tiredness/low energy  diarrhea As well, some patients might have high blood levels of liver enzymes such as alkaline phosphatase. Researchers in North America are conducting clinical trials of drugs that may be used to treat patients including:  azithromycin  clarithromycin  rifabutin Some researchers think that low doses of corticosteroids (1 to 4 mg/day) such as dexamethasone may be useful in relieving some of the symptoms of MAC infection. * STUDY DETAILS All subjects had less than 11 CD4+ cells, unintentional weight loss and fever despite treatment with a combination of 3 antibiotics, one of which was clarithromycin. Technicians detected high blood levels of a liver enzyme (alkaline phosphatase) and low blood levels of protein in the blood samples of subjects. They received 1 to 4 mg/day of dexamethasone orally. * RESULTS Subjects had an average weight increase of 31 pounds which lasted for an average of 5 months. Fever decreased as did liver enzyme levels. Blood levels of protein increased. Four subjects received therapy for an average of 9 months, until they died. * TOXICITY Doctors stopped giving one subject steroids because he developed the sight-threatening infection CMV retinitis. The drug may also have caused oral yeast infections and possible damage to the pancreas gland in 2 subjects, one of whom developed high blood levels of sugar. Four of these subjects died-perhaps because of several infections that may have been made worse by the corticosteroid. That one subject developed CMV retinitis is not surprising. Doctors in England reported that HIV-infected subjects who used high doses of corticosteroids seemed more likely to develop CMV retinitis. (For details please see TreatmentUpdate 42). The doctors treating this group of 4 subjects suggested that subjects who are using the antibiotics rifampin and 'related' drugs (rifabutin, rifamycin) may need higher doses of corticosteroids. REFERENCES: 1. Wormser GP, Horowitz H and Dworkin B. Low-dose dexamethasone as adjunctive therapy for disseminated Mycobacterium avium complex infections in AIDS patients. Antimicrobial Agents and Chemotherapy 1994;38(9):2215-2217. II INFECTION FIGHTERS A. Preventing PCP-Bactrim/Septra 3 days weekly * BACKGROUND Although guidelines by the US Public Health Service suggest that HIV-infected patients should receive preventative doses of Bactrim(R)/Septra(R) every day, some doctors disagree with this schedule. (Bactrim/Septra (B/S) are the brand names of a combination of 2 antibiotics. The regular dose [also called single strength] has 80 mg trimethoprim and 400 mg sulphamethoxazole. The double strength (DS) has 160 mg trimethoprim and 800 mg sulphamethoxazole.) A few studies suggest that using B/S 3 times per week may be as effective as daily use in preventing PCP. Intermittent doses of B/S may be less toxic for patients and may delay the growth of microbes which are resistant to that drug. Researchers in California have been conducting experiments on HIV-infected subjects with B/S and AZT. Preliminary results from their work suggest that B/S three times weekly is easier to tolerate than daily doses. * STUDY DETAILS Researchers used data from 107 HIV-infected subjects who entered the study with less than 200 CD4+ cells (the average CD4+ cell count was about 140 cells). Subjects who had severe and life-threatening reactions to sulpha drugs were not allowed to enter this study. Subjects randomly received either B/S single strength twice daily or the same dose taken on Monday/ Wednesday/Friday. Some subjects also received 10 mg/day leucovorin, an artificial form of the B-vitamin folic acid, to protect their bone marrow from the side effects of AZT and B/S. Initially subjects received 1 g/day of AZT which was later reduced to 500 mg/day. Researchers did not release details on the sex of subjects. * RESULTS Forty-two percent (42%) of 52 subjects receiving daily B/S had to stop taking that drug because of bone marrow toxicity. For subjects taking B/S thrice weekly 24% had to stop for the same reason. Using leucovorin did not seem to have any effect in reducing bone marrow toxicity or influencing which group of subjects left the study. However, researchers noted that subjects who received leucovorin were 6 times less likely to develop bone marrow toxicity than subjects not taking that drug. This difference was not statistically significant. Subjects taking B/S thrice weekly were more likely to keep taking the drug (68%) than subjects taking the daily dose (51%). This difference between the two arms of the study was statistically significant; that is, not likely due to chance alone. * TOXICITY The most common side effect was "headache". Problems with intestinal toxicity were reported, with "nausea" being the most common. Fatigue was also another side effect in a small number of subjects. Interestingly, serious bone marrow damage did not occur. A small number of subjects stopped using B/S because they developed several side effects including 'neurological complaints (the doctors did not provide further details), fever and fatigue'. The researchers checked a number of factors (including high doses of AZT versus low; AIDS versus ARC) but these did not help them predict which subjects would develop drug toxicity. * WHY WAS THERE A DIFFERENCE? The researchers are not sure why subjects receiving thrice weekly B/S were better able to tolerate the drug than those taking it every day. No subject receiving B/S developed PCP. One subject developed the life-threatening brain infection 'crytpo' (Cryptococcus neoformans) and another a bacterial infection. No subject developed infections such as toxo or MAC which can be affected by B/S. As subjects taking B/S three times weekly were much more likely to continue taking their drug than those who received it daily, this may have an impact on who develops infections such as PCP/toxo over the long term. REFERENCES: 1. Bozzette SA, Forthal D, Sattler FR, et al. The tolerance for Zidovudine plus thrice weekly or daily trimethoprim-sulfametnoxazole with and without leucovorirl for primary prophylaxis in advanced HIV disease. American Journal of Medicine 1995;98:177-182. B. Toxo--standard treatment * BACKGROUND One of the more common life-threatening brain infections seen in patients with AIDS is toxo (toxoplasmosis). The parasite that causes toxo (T. gondii) is found in "some birds and [other animals] including humans." Humans become infected with the parasite while they are in the womb or when they eat "raw or undercooked meat", or accidentally eat feces from infected cats. People can also be infected through blood transfusions. Although T. gondii can infect the brain, other parts of the body - eye, heart, lung - may also become infected. * SIGNS/SYMPTOMS OF TOXO As T. gondii "can infect any cell in the brain" patients can have a variety of symptoms. Moreover, initial symptoms may be mild at first but become worse over a period of weeks as the infection spreads. Magnetic and X-ray scans of the brain can detect lesions that suggest toxo. Signs/symptoms can include:  seizures  fever  coma  confusion  problems understanding speech  weakening 'arm strength'  headache  problems with speech/vision  muscle control  loss of control of muscles on one side of the body  problems walking As CMI (cell-mediated immunity) weakens, the immune system is less able to keep infections under control. As well, the parasite that causes toxo seems able to further weaken cells of the immune system when they find the parasite. Toxo is more likely to happen in patients with less than 200 CD4+ cells. Some patients may have anti-toxo antibodies in their blood and are at increased risk for developing toxo. * STANDARD TREATMENT Patients usually receive a combination of 2 drugs- pyrimethamine and sulphadiazine. On the first day doctors may prescribe 200 mg/day of pyrimethamine which is later reduced to 50 or 75 mg/day. Patients may also receive sulphadiazine in doses of 4 to 6 grams/day. This therapy usually continues for 6 weeks. Doctors may also prescribe between 5 and 10 mg/day of the B-vitamin folic acid to protect the bone marrow from the toxicity of the antibiotics. Sulphadiazine may also affect the kidneys. Some doctors stop prescribing AZT because it may weaken the effect of pyrimethamine. * CLINDAMYCIN AND OTHER DRUGS As some patients may not be able to tolerate sulpha drugs, doctors may substitute 2.4 to 4.5 g/day of clindamycin for sulphadiazine. In some cases clindamycin may be sent directly into patients' veins especially if they have nausea and vomiting. Treatment with Bactrim/Septra or Mepron may be useful for some patients who cannot tolerate pyrimethamine. * MAINTENANCE Patients will need to keep taking antibiotics to suppress the infection for the rest of their lives. For maintenance doctors may use between 25 and 50 mg/day of pyrimethamine and between 2 and 4 g/day of sulphadiazine. Patients who cannot tolerate sulpha drugs may use a minimum of 1200 mg/day of clindamycin. Some doctors prescribe Bactrim/Septra 1 DS (double strength) tablet taken every day or 3 days weekly. Others may use dapsone (75 to 300 mg/ week) with or without pyrimethamine (50 to 200 mg/ week). Doctors may prescribe between 1 and 15 g/day of clarithromycin with minocycline 100 to 200 mg/ day. * EXPERIMENTAL DRUGS A number of research teams are conducting laboratory experiments with toxo-infected mice testing combinations of various antibiotics. Promising combinations may include pyrimethamine with:  clarithromycin or azithromycin or roxithromycin  Mepron(R)/Wellvone(R)  rifabutin and/or clindamycin and/or Mepron REFERENCES: 1. Luft BJ, Hafner R, Korzum MS, et al. Toxoplasmic encephalitisin patients with the Acquired Immunodeficiency Syndrome. New England Journal of Medicine 1993;329(14):995-1000. 2. St. Georgiev V. Management of toxoplasmosis. Drugs 1994;48(2):179-188 3. Smith G. Treatment of infections in the patient with Acquired Immunodeficiency Syndrome. Archives of Internal Medicine 1994;154:949-973. 4. New L and Holliman RE. Toxoplasmosis and Human Immunodeficiency Virus (HIV) disease. Journal of Antimicro- bial Chemotherapy 1994;33:1079-1082. 5. Haque S, Khan I, Hague A and Caspar L. Impairment of tbe cellular immune response in acute murine toxoplasmosis: regulation of interleukin 2 production and macrophage-mediated inhibitory effects. Infection and Immunity 1994;62(7):2908-2916 6. Alder J, Hutch T, Meulbroek J and Clement J. Treatment of experimental Toxoplasmic gondii infection by clarithromycin-based combination therapy with minocycline or pyrimethamine. Journal of Acquired Immunodefieieney Syndrome 1994;7(11):1141-1148. 7. Bran-Pascaud M, Chad F, Simonpoli A-M, et al. Experimental evaluation of combined prophylaxis againstmurine pneumocystosis and toxoplasmosis. Journal of Infectious Diseases 1994; 170:653- 658. 8. Aerugo F, Silver T and Remington J. Rifabutin is active in murine model of toxoplasmosis. Antimicrobial Agents and Chemotherapy 1994;38(3):570-575. C. Toxo: treatrnent with clarithromycin and minocycline * STUDY DETAILS Doctors in this study used 6 men and 2 women, all HIV-infected, having an average CD4+ cell count of 18 cells. All had toxo and treatment with pyrimethamine, sulphadiazine and clindamycin caused serious side effects. X-ray scans of their brains detected lesions suggestive of toxo in 7 subjects. In one subject the infection was in the lung. Six subjects received clarithromycin in doses ranging from 3/4 to 2 g/day and 200 mg/day of minocycline. Subjects received the combination for an average of 9 weeks. During this period of time they also received 75 mg/day of pyrimethamine. The researchers reported results from 6 subjects. * RESULTS-SYMPTOMS Symptoms cleared in 4 subjects, 3 of whom had 'minimal' brain infection according to the X-ray scans. The 4th subject also lost symptoms and his X-ray scan revealed no lesions in the brain. The researchers note that the recovery seen in these 4 subjects may have been helped by their previous use of standard anti-toxo therapy. Two of the remaining 6 subjects died while receiving anti-toxo treatment. The cause of death was a bacterial infection in one subject and HIV-damage to the brain of the other subject. * RESULT-MAINTENANCE THERAPY Surviving subjects received clarithromycin 1 to 1.5 g/ day and between 100 and 200 mg/day of minocycline. Three subjects also received 1 tablet of Bactrim/Septra (single strength). Researchers monitored subjects for an average of 7 months. Five subjects did not have further symptoms of toxo. The sixth subject who was also supposed to be taking Bactrim/Septra had another bout of toxo and the researchers suggest that he was not taking that drug. One subject died from complications caused by a stroke about 7 months after he recovered from toxo. Researchers reported no side effects from the combination of clarithromycin and minocycline combination. The study doctors stated that clarithromycin-minocycline may be an option for subjects who have toxo and do not benefit from standard therapy. As well, combination therapy seems to suppress the infection once subjects recover. The researchers suggest that more studies are needed to test regimens such as theirs for patients with toxo. Other researchers in California are conducting experiments and trying to understand why the immune system fails to keep the parasite that causes toxo under control. Doctors in the USA have recently reported their experience with minocycline. These doctors gave their patient intravenous doxycycline (minocycline) 200 mg/day in addition to intravenous clindamycin 900 mg 3 times daily and oral pyrimethamine 50 mg/day. This combination allowed their patient to recover from toxo. REFERENCES: 1. La Casein F, Scapha D, Perron C, et al. Clarithromycin-minocycline combination as salvage therapy for toxoplasmosis in patients infected with Hurnan Immunodeficiency Virus. Antimicrobial Agents and Chemotherapy 1995;39(1):276-277. 2. van de Ven ES, Vree T, Milkers W, et al. In vitro effects of sulfadiazine and its metabolites alone and in combination with pyrimethamine on Toxoplasma gondii. Antimicrobial Agents and Chemotherapy 1995;39(3):763-765. 3. Indorf AS and Pogrom P. Use of doxycycline in the management of a patient with Toxoplasmic encephalitis. AIDS 1995;8(1):1633-1634. D. Roxithromycin for MAC/TB and toxo * BACKGROUND Although there are several drugs that doctors can use to treat and prevent the life-threatening lung infection PCP, the brain infection toxo (toxoplasmosis), tuberculosis (TB), and MAC, all these drugs have side effects. In some patients these side effects are mild and in others they are not. Doctors are experimenting with a variety of drugs to see which is right for their patients. In the late 1980s doctors in Germany reported that treatment with between 2 and 3 grams/day of the antibiotic erythromycin was effective against PCP. Researchers in the EU have been experimenting with drugs 'related' to erythromycin such as azithromycin and clarithromycin. We now report on another related drug, roxithromycin. * STUDY DETAILS Researchers enrolled 52 HIV-infected adults (46 men, 6 women) who had less than 200 CD4+ cells (the average was about 133 cells). At the time subjects entered the study none had any life-threatening infections. Researchers randomly assigned subjects to one of 3 groups or 'arms'. Eighteen subjects received 300 mg/month of aerosol pentarnidine (AP), 17 others received a combination of aerosol pentamidine and roxithromycin (300 mg 3 times daily once per week); and another 17 subjects received roxithromycin in the same dose and schedule as in the other group. * RESULTS Subjects given roxithromycin developed life-threatening infections much later than subjects given AP. As well, subjects given roxithromycin were also less likely to develop the life-threatening brain infection toxoplasmosis. These 2 differences were statistically significant; that is, not likely due to chance alone. Subjects receiving roxithromycin were less likely to develop TB and MAC infections. Fungal infections in the throat occurred evenly among the groups of subjects. For the purposes of this report we will include the subjects receiving the combination of AP and roxithromycin with the others who received roxithromycin alone as there were no statistically significant differences between the 2 groups. For the listing of deaths in this study we report the number for each of the three arms. * INFECTIONS AND DEATH: WHO GOT PCP, TOXO, TB/MAC, AND WHO DIED? PCP: 3 subjects on AP 1 subject on roxithromycin toxo: 5 subjects on AP 1 subject receiving roxithromycin TB/MAC: 4 subjects on AP No subjects on roxithromycin Deaths: 4 subjects on AP 3 subjects on AP and roxithromycin 3 subjects on roxithromycin * TOXICITY Doctors found that AP was 'well tolerated' by subjects. Researchers had to stop giving roxithromycin to 5 subjects who had "nausea, abdominal pain and skin allergies" and to 1 other subject who had high blood levels of liver enzymes suggesting some liver damage. Upon investigation the researchers found that this last subject had hepatitis C which may have caused the high levels of liver enzymes. They noted that this subject suffered no symptoms of liver (or any other) toxicity. Six weeks after he stopped taking roxithromycin his liver enzyme levels fell to normal. As soon as subjects developed life-threatening infection(s), researchers stopped giving them roxithromycin. Causes of death in this study included various bacterial infections, unintentional weight loss and one case of toxo. No subject died from PCP, TB or MAC infection. * ROXITHROMYCIN As many people in Western Europe have greater exposure to the parasite that causes toxo, it is interesting that more subjects receiving roxithromycin did not develop symptoms of toxoplasmosis. The researchers suggest that another study with more patients should be conducted to confirm their findings. Based on their data the researchers suggest that roxithromycin 900 mg/day once a week protects subjects for at least 8 months from developing toxo. The researchers note that the proportion of subjects who stopped taking roxithromycin because of toxicity is similar to withdrawal rates seen in other trials using Bactrim/Septra as PCP prevention. Roxithromycin in this study was supplied by Roussel-Uclaf. REFERENCES: 1. Durant J, Hazime F, Carles JM, etal. Prevention of Pneumocystis carinii pneumonia and of cerebral toxoplasmosis by roxithromycin in HIV-infected patients. Infection 1995;23 (supplement 1 ):s533- sS38. E. Predicting who will get toxo * STUDY DETAILS Researchers in France used data collected on 499 subjects to try and find out which subjects would develop the life-threatening brain infection toxo. At the time these subjects entered the study none had toxo. The average CD4+ cell count was 70 cells. About 60% of subjects had less than 50 CD4+ cells. Technicians tested the blood samples from 410 subjects to find antibodies against toxo. A total of 298 had anti- toxo antibodies. When subjects entered the study 80 received Bactrim/Septra as preventative therapy against PCP/toxo; '34 received pyrimethamine'; 19 received dapsone; '11 received [Fansidar@]' and 1 received pyrimethamine-sulphadiazine. * RESULT-SURVIVAL Researchers monitored subjects for an average of 1 year during which 16% (83) subjects developed toxo; 75 had it as a brain infection, 7 had the infection in their eyes and 1 developed toxo in the lungs. Altogether, 67% of the 499 subjects died while in this study. * CD4+ CELL COUNTS In this study subjects with CD4+ cell counts of less than 100 cells were at high risk for developing toxo. This link between low CD4+ cell eounts and toxo was statistically significant; that is, not likely due to chance alone. When subjects developed toxo they had an average CD4+ cell count of 31 cells. About 18% of subjects who had less than 100 CD4+ cells when they entered the study developed toxo. By contrast, only 9% of subjects who entered the study with CD4+ cell counts of at least 100 cells developed toxo. * ANTIBODIES Subjects who had anti-toxo antibodies in their blood were very likely to develop toxo while in the study. Over a period of 1 year 21% of these subjects developed toxo compared to none of the subjects without these antibodies. This difference was statistically significant. * BACTRIM/SEPTRA REDUCES THE RISK "Three of 80 [subjects] receiving Bactrim/Septra and 72 of 419 subjects not receiving Bactrim/Septra developed toxo in their brains". This was statistically significant. "One of 34 [subjects] receiving pyrimethamine and 74 of 465 subjects who [did not use] pyrimetharnine when they entered the study developed toxo." This difference was also statistically significant. * CHECKING THE RISKS There were 149 subjects with less than 100 CD4+ cells who had anti-toxo antibodies but did not receive antibiotics. Forty-eight (32%) of these subjects developed toxo in their brains. Of the 74 subjects with less than 100 CD4+ cells who had antibodies against toxo but did receive antibiotics, 5 (7%) developed toxo in their brain. This difference was also statistically significant. * SURVIVAL All subjects who developed toxo died at some point during the study. Taking antibiotics did not seem to affeet survival. When researchers adjusted their ealeulations to take into aceount different CD4+ eell eounts, again there was no difference in survival. REFERENCES: 1. Oksenhendler E, Charreau I, Tournerie C, et al. Toxoplasma gondii infection in advanced HIV infection. AIDS 1994;8:483-487. III TOXICITY A. Caution about thalidomide * A WARNING Researchers at Cambridge University have been conducting experiments on healthy humans, 10 of whom received the tranquilizer thalidomide 200 mg/day and 6 others who did not. Results of immunologic tests clearly showed that thalidomide appear to 'switch' the immune response to one based on humoral immunity where antibody-producing B-cells play a major role. This 'switch' may, in the long term, eause serious eonsequences. For details please see TreatznentUpdate 56. The Cambridge researchers warn that thalidomide may weaken the immune system's ability to fight life-threatening infections. REFERENCES: 1. McHugh SM, Rifkin R, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen-and antigen-stimulated human peripheral blood mononuclear cell cultures. Clinical and Experimental Immunology 1995;99:160-167. B. Reducing the toxicity of sulpha drugs * BACKGROUND Sulpha drugs are often the first therapies doctors consider when treating HIV-infected patients with the life-threatening lung infection PCP or the brain infection toxo (toxoplasmosis). Unfortunately many patients with HIV/AIDS tend to 'experience' serious side effects when given these drugs. Researchers are not sure why this happens. It may be that the way HIV-infected subjects 'process' drugs leads to the production of compounds that cause these side effects. * ANTIOXIDANTS In laboratory experiments with cells, treatment with antioxidants appears to reduce the production of toxic compounds from sulpha drugs. This may not be surprising because several research teams have reported that subjects with HIV/AIDS have less-than-normal levels of certain substances used by the body to make its detoxifying enzymes. Researchers and their patients are experimenting with a number of antioxidants that the body cannot make (vitamins C and E and beta carotene) and taking supplements of materials (sulphur-containing amino acids - cysteine, methionine, the minerals selenium, copper, manganese and zinc) needed to make the body's antioxidant enzymes. Some researchers are conducting experiments where at first subjects receive small doses of sulpha drugs which gradually increase to the full treatment dose--a process called desensitization. C. Experiments in France * DOSE Researchers in Paris reported results from 8 men and 4 women whose average CD4+ cell count was about 100 cells. These subjects had been using Bactrim/Septra (containing 160 mg of trimethoprim and 800 mg of sulphamethoxazole) to prevent infections such as PCP/toxo (11 of them were taking 160/800 - one double strength tablet as PCP prevention). The remaining subject took a 'treatment' dose (640 mg trimethoprim/ 3200 sulphamethoxazole mg/day). Half of the subjects developed side effects within 15 days of using Bactrirn/Septra. Eleven subjects had a rash without fever or [puritis]. * THE PROTOCOL The researchers kept the subjects in hospital for 2 days so that if a life-threatening reaction to Bactrim/Septra occurred, subjects' lives could be saved. Researchers started giving subjects small doses of liquid Bactrim/Septra every 3 hours. The first dose had 0.2 mg of trimethoprim and 1 mg sulphamethoxazole. Eventually subjects would take 80 mg trimethoprim and 400 mg/day of sulphamethoxazole (both drugs) once daily. The researchers did not raise the dose of Bactrim/Septra nor did subjects receive any new drug for the first month after they had been desensitized. Subjects did not receive any antihistamines or corticosteroids. * RESULTS Four subjects developed side effects - rash - despite the desensitization protocol. Another 4 subjects developed side effects within the first month after being desensitized. Ten months after being desensitized only 4 subjects could continue to use Bactrim/Septra. Researchers could not understand why some subjects remained desensitized. They checked the CD4+ cell counts amongst the subjects but there were no statistically significant differences. This research team suggests that a longer period of desensitization may be more useful. REFERENCES: 1. Bachmeyer C, Salrnon D, Guerin C, et al. Trimethoprim-sulphamethoxazole desensitization in HIV-infected patients: an open study. AIDS 1995;9(3):299-300 2. Rieder MJ, Krause R, Bird LX and Dekaban G. Toxicity of sulfonamide-reactive metabolites in HIV-infected HTLV-infected, and non-infected cells. Journal of Acquired Immunodeficiency Syndromes and Human Retrovirology 1995;8(2):134-140. IV TESTING A. Using skin tests to predict infections * BACKGROUND In general, most HIV-infected people have decreasing numbers of CD4+ cells over time. Measuring CD4+ (and CD8+) cell counts can be useful because doctors can make decisions about when to begin giving patients drugs to prevent certain infections. By themselves, CD4+ cell counts do not provide a detailed report on the ability of the immune system to resist infections. Many of the life-threatening infections seen in AIDS occur because T cells have lost a very important defense - CMI (cell-mediated immunity). CMI is particularly useful in fighting microbes that can infect and 'hide' inside cells. In such cases, antibodies alone will not be useful and may even help spread the infection. Counting CD4+ cells may provide a sense of certainty; something which people can grasp and easily understand. Performing skin tests may not give people that same sense of precision. Nonetheless, skin testing is one of the few ways to measure CMI. * WHICH SKIN TESTS? Nurses injected a small amount of protein from various microbes under the skin. In subjects with normal levels of CMI, within 48 to 72 hours after the injection there is a reaction at the injection site. The reaction is usually swelling and redness and the skin becomes raised. This delayed reaction is why these tests are called DTH (delayed-type hypersensitivity). In subjects who have lost some level of CMI the reaction may be reduced. In subjects with very low levels of CMI there may be no reaction. The immune system of these subjects (no reaction) is described by researchers as 'anergic' or exhausted. If performed over a period of time skin test results can reveal what is happening to the body's ability to produce CMI. For this study, researchers decided that subjects whose skin produced a 10 mm by 10 mm reaction to the injection of protein (from microbes) had a 'positive' reaction. * STUDY DETAILS Researchers at military bio-medical centres in the USA have been conducting experiments on HIV-infected subjects. In one experiment researchers conducted extensive laboratory tests on subjects over a five-year period - 1985 to 1990. In this experiment researchers also measured CMI using skin tests. The study doctors analysed data on 600 subjects, 94% of whom were male and 6% female. Their average age was 28 years. At some point during their study 28% of subjects used AZT. * RESULTS  about 60% of subjects who had less than 200 CD4+ cells were completely 'anergic'; their level of CMI was extremely low.  approximately '96% of [subjects] with more than 400 CD4+ cells had [some level of CMI]' These subjects reacted to 'at least one skin test'. These differences in levels of CMI were statistically significant; that is, not likely due to chance alone.  '86% of subjects with more than 400 CD4+ cells were able to [react] to at least 2 skin tests compared to '45% of subjects' with less than 400 CD4+ cells.  on average, subjects who could only react to 1 of the 5 proteins (with which they had been injected) had reduced levels of CD4+ cells compared to subjects who had '2 or more [skin reactions]'. Again, this difference was statistically significant. Researchers looked at skin test results and compared them to the appearance of life-threatening infections. They found that subjects who had the following test results developed a life-threatening infection/cancer in the following time:  no positive tests - 43 months  1 positive result - 51 months  2 or more positive tests - 55 months These differences in time to infections/cancers were statistically significant. As well, DTH responses were clearly linked to the development of AIDS even in subjects who had relatively high CD4+ cell counts when they entered the study. Moreover, skin test responses alone could be used to predict which subjects would develop AIDS. * OTHER GROUPS Some researchers think that other groups of HIV-infected subjects, such as drug users, may have weaker CMI than (in this study) gay/bisexual men, and that this population may have different skin test results. Other researchers suggest that a smaller measurement (5 mm x 5 mm) could have been used as a cut-off point. In the article below we report results on gay/ bisexual men, drug users (both HIV-infected and non-HIV-infected) as well as heterosexual women. REFERENCES: 1. Blatt SP, Hendrix CW, Butzin CA, et al. Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients. Annals of Internal Medicine 1993;119(3):177-184. B. Skin tests on HIV-infected and non-HIV-infected people * TESTING FOR TB As part of tuberculosis (TB) control programmes in the USA, public health workers perform a variety of tasks such as making sure that their patients take their antibiotics as instructed, providing counselling and testing their patients to see if they have been infected with the bacteria that cause TB. Nurses can inject a small amount of protein from TB-causing bacteria called PPD (purified protein derivative) and watch for a reaction 2 days later. This reaction is called delayed-type hypersensitivity (DTH). A reaction to PPD, swelling and redness indicates that the person has been exposed to TB-causing bacteria or has been vaccinated with the TB vaccine BCG. This reaction depends on one type of immune response caUed CMI (cell-mediated immunity). * ANERGY Under constant attack by HIV and other microbes over many years CMI weakens and infections grow out of control. In people with weak or 'exhausted' immune systems there may be no reaction to PPD or other proteins and these people are called 'anergic'. This lack of reaction to PPD creates problems for health care workers when trying to find out if their patients have been infected with TB. One way to try and deal with this problem of no reaction to PPD is to also inject them with 'at least 2 [other proteins that cause DTH reactions)'. In practice this means that health care workers inject patients with proteins from bacteria, fungi or viruses at the same time they receive PPD injections (each in its own spot on skin). In this way if patients react with swelling and redness to the other proteins but don't react to PPD, it is very likely that they have not been infected by TB-causing bacteria (these patients do not have symptoms of TB). To test this idea, researchers across the USA have been performing tests of DTH on a variety of subjects for which we provide details. * STUDY DETAILS Over a 1 6-month period researchers enrolled over 1,300 subjects and here is the subject profile at the start of the study:  86% male  70% gay/bisexual  25% injection drug users  5% heterosexual women  68% white, 24% black and 6% hispanic  50% of HIV-infected subjects had a CD4+ cell count of 410 cells  For 50% of non-HIV-infected subjects the equivalent was 889 cells Although most of the subjects were HIV-infected, researchers enrolled a smaller but similar group of non-HIV-infected subjects to use for comparison. * RESULTS  as expected, non-HIV-infected subjects were more likely to have DTH than HIV-infected subjects, a difference that was statistically significant  HIV-infected and non-infected injection drug users had similar rates of DTH reactions to PPD  Injection drug users (both HIV-infected and non- infected) were 3 times more likely to have a reaction to PPD than gay/bisexual men. This difference was statistically significant.  Among non-HIV-infected subjects, anergy (a lack of responses to the various proteins used) occurred in 44% of injection drug users and 16% of gay/bisexual men. This difference between the 2 groups was statistically significant  A lack of response to all 4 proteins (anergy) occurred in the same proportion of subjects across all groups of HIV-infected subjects.  About 11% of heterosexual women had DTH to PPD  non-HIV-infected gay/bisexual men were 3 tirnes more likely to have DTH to PPD compared with similar HIV-infected men. This difference was also statistically significant. * CD4+ AND DTH There was a general trend for fewer DTH responses as CD4+ counts fell among HIV-infected subjects. This trend was statistically significant. * FOCUS ON TB In this study, among 716 subjects (who received all 4 microbial proteins) there was no link between responding to PPD and reactions to other proteins tested. Older subjects, and those who received the TB vaccine BCG or who had reacted to PPD in the past were more likely to have a 'positive' skin test result to PPD. No subject with less than 100 CD4+ cells reacted to PPD in this study. * FOCUS ON AN EXHAUSTED IMMUNE SYSTEM (ANERGY) The researchers in this study found that anergy was more likely to occur in:  HIV-infected subjects  HIV-infected subjects with less than 200 CD4+ Anergy was less likely to occur in:  HIV-infected subjects with at least 600 CD4+ cells  non-HIV infected subjects The researchers found that 'overall, HIV-infected [injection] drug users were no more likely to be anergic than HIV-infected gay/bisexual men'. Women did not seem to be any more anergic than men. Interestingly, results from this study were similar to another which used data from over 2,000 Haitian subjects. There are problems comparing results from studies which used different tests and different ways of interpreting skin test results. * DEVELOPING TB According to the study doctors, results from earlier studies 'suggest that many HIV-infected people have a positive [reaction to PPD injections] months to years before [symptoms of TB appear].' They add that 'most cases of TB develop [when patients can react to skin tests using PPD].' They add that most cases of HIV-related TB are caused by reactivated and not new infections. * WHAT TO DO? Testing anergic subjects with other proteins might spare some people from being given anti-TB medication (assuming that these people had been TB-infected despite a negative reaction to PPD) isoniazid and its toxicities. The researchers found that subjects were likely to react to PPD regardless of any other reaction to other proteins. In this study, anergy to PPD started when subjects' CD+ cell counts fell below 400 cells. The study doctors suggest that in the absence of highly accurate tests that can predict who will get TB, better ways of detecting TB bacteria and less toxic therapies, early skin (in HIV-infected subjects) should be done on a regular basis 'even in patients with low CD+ cells'. Skin testing kits, such as the 'Multitest', sold by Pasteur-Merieux Serum et Vaccins. REFERENCES: 1. Markowitz N, Hansen NI, Wilcosky TC, et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Annals of Internal Medicine 1993;119(3):185-193. Copyright (c) 1995 - Treatment Update. Noncommercial reproduction encouraged. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+