Subject: Treatment Update #29 Date: Dec 1991 (835 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T U P D A T E && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& [ Electronic Distribution made possible by The GAY BLADE, Toronto, Ontario -- (416) 882-4800 -- ORAnet node 171 or *GAYCOM* node 69: 1/202 ] TreatmentUpdate 29 - December 1991 Community AIDS Treatment Information Exchange Reseau Communautaire D'Info-Traitements Sida Permission granted for noncommercial reproduction on condition that direct quotations are cited. CONTENTS: [items are separated by "*****" for this display] I. ANTI-HIV AGENTS A. AZT and ddC B. AZT and Nutritional Complications II. IMMUNOMODULATORS A. Imreg-1 Improvements in Quality of Life B. Specific Nutrients and HIV/AIDS C. Changes in Zinc and Copper D. Vitamin B6 and Immune Function E. Vitamin B12 and Quality of Life F. Folic Acid and Cervical Cancer G. Helpful Sugar from Yeast H. "Friendly" Yeast for Diarrhea? III. INFECTION FIGHTERS A. Sparfloxacin for TB and MAC IV. TEST A. Colposcopy Study Raises Questions About Pap Smears ********** I. ANTI-HIV AGENTS A. AZT and ddC Over the long term, the beneficial effects of AZT are known to wear off, and patients experience declines in CD4+ cell counts and more opportunistic infections. The reasons for the eventual failure of AZT to delay disease progression are uncertain, but they may be related to the development of drug-resistant virus, to the increasing toxicity of the drug over time, or to other, as yet unknown, factors. One potential alternative to the use of AZT alone (monotherapy) is a combination which, in the short-term, appears beneficial is AZT with ddC; in some laboratory experiments with viruses and cells, the combination appears to have greater anti- HIV effect then either drug abuse. Preliminary results of studies in the USA were presented in TreatmentUpdate 24 and detailed results are now available. Fifty-six subjects were enrolled into a study whose aim was to test various dose combinations of AZT and ddC. All subjects had fewer than 201 CD4+ cells, were never supposed to have used anti-retroviral agents, had AIDS or advanced ARC (defined as oral yeast infections, unintentional weight loss of at least 10% of body weight, persistent diarrhea, and fever). All subjects received aerosolized pentamidine for the prevention of PCP. The various combinations used in the trial were meant to be taken orally, every 8 hours: group 1 -- AZT 100 mg and ddC 0.01 mg/kg of body weight, group 2 -- AZT 200 mg and ddC 0.005 mg/kg., group 3 -- AZT 50 mg. and ddC 0.005 mg./kg., group 4 -- AZT 100 mg. and ddC 0.01, group 5 -- 200 mg. and ddC 0.01 mg/kg., and group 6 -- 50 mg. of AZT without ddC. Doses were reduced as required. At least half the subjects remained in the study for up to 40 weeks; a total of 18 subjects were removed from the trial for various reasons, including the appearance of opportunistic infections and/or cancer within the initial 8 weeks of the study (9 subjects), self-withdrawal (4 subjects), not taking the study drugs as directed (4 subjects), and death (1 subject). Two subjects developed and pain in the lower extremities, likely due to ddC toxicity, and were removed from the study. Another 4 subjects developed mild peripheral neuropathy, but the study investigators decided that this was not caused by ddC. Ten subjects experienced various anemias at some point. The use of ddC did not appear to increase the bone marrow suppressive effect of AZT. The average CD4+ count increased in all groups during the first 4 weeks. The increase was not statistically significant in the 6 groups. CD4+ cell decline rates in groups 2 and 5 were slower than in group 6. According to the investigators, several of the combinations produced "persistent increases in CD4+ lymphocyte counts above pre-treatment values for at least 10 months in many patients receiving the high-dose regimens. Although these results must be interpreted with caution because of the small study sample and the possible effects of differences in dropout rates among the regimens, the response rates of CD4+ lymphocytes seen in our patients differ sufficiently from those reported in previous studies to merit comment." The investigators suggest several reasons for the improved immune response to the drug combinations. First, it is possible that the use of AZT and ddC together had an additive effect, resulting in sustained HIV suppression, greater than would occur with AZT alone. Second, the combination may have delayed the appearance of drug resistant virus. The doctors plan to use regimen 5 (AZT 600 mg/day with ddC 0.03 mg/kg/day) for future studies Doctors disagree on the best way to deal with AZT- resistant strains of HIV; some favour combinations, others think that monotherapy with another agent may be best. Although regimen 5 appears promising, whether the increases in CD4+ cell counts result in significantly increased survival compared to survival with AZT monotherapy remains to be demonstrated in controlled clinical trials. REFERENCES: 1. Meng T-C, Fischl MA, Boota AM et al. Combination therapy with Zidovudine and dideoxycytidine in patients with advanced Human Immno- deficiency Virus infection: a phase I/II study. Annals of Internal Medicine 1992: 116(1): 13-20. ***** B. AZT and nutritional complications While the adverse effects of AZT on bone marrow are well known, the drug may also alter the balance of nutrients in the body -- use of AZT has been associated with reduced levels of the element selenium and vitamin B2. Studying the effect of AZT -- or other anti-retrovirals -- on nutrients in the body is important because deficiencies of many vitamins and minerals can have an unfavorable impact on the immune system. As part of a larger, one-year study of 130 subjects on the role of nutrition on disease progression in people with HIV infection, researchers at the Universities of Miami and Alabama also investigated the effect of AZT on the nutritional status of a smaller group of subjects. All 37 subjects were male and apart from persistently swollen lymph glands had no symptoms. Of the 37, 15, whose CD4+ count was approximately 350 cells, were given AZT in doses of between 500 to 1200 mg/day. These 15 subjects were compared to a control group of 22 subjects with a similar CD4+ cell count who were not given AZT. At the start of the study (baseline), no significant differences in nutrient levels between the groups were noted. Both groups had similar dietary histories at baseline. The researchers found that a large number of subjects on AZT had decreased blood levels of zinc despite "adequate" zinc in their diets. The exact cause of this deficiency is uncertain, but may be due to several factors. Changes in metabolism when recovering from infections, and increasing loss and replacement of cells may increase zinc requirements. Interestingly, the enzymes used to convert AZT into its active or anti-viral form require zinc. Thus, use of AZT may place additional demand on the available zinc in the body. Among the AZT-treated subjects who had "adequate" blood levels of zinc, immune functions necessary to respond to invading organisms seemed better than those in subjects using AZT who did not have "adequate" blood levels of zinc. Although there were also decreases in the blood levels of copper, these did not appear to hamper immune functions. The interplay between copper and zinc in the body is complex and is discussed in further detail later in this issue of TreatmentUpdate. So far, there have not been large, randomized trials conducted to investigate the effect of zinc supplementation on disease progression in AZT users. REFERENCES: 1. Baum MK, Javier JJ, Mantero-Atienzs et al. Zidovudine associated adverse reactions in a longitudinal study of asymptomatic HIV-1 infected homosexual males . Journal of Acquired Immune Deficiency Syndromes 1991;4(12): 1218-1226. ***** II. IMMUNOMODULATORS A. Imreg 1-Improvements in quality of life In a large, 6-month, randomized, placebo-controlled trial in subjects with ARC and Kaposi's sarcoma, Imreg 1, an extract of white blood cells, has been shown to delay the onset of AIDS. (For details of this trial see TreatmentUpdate 24.) One of the recruiting centres for the trial followed subjects beyond the initial 6 months and has reported its observations. The subjects enrolled at this centre in California had ARC (45 subjects) or Kaposi's sarcoma (4 subjects). All were HIV- infected and immune-suppressed. Subjects with a history of shingles were also included in the trial. One unit of Imreg 1 or placebo was injected under the skin of subjects once every 2 weeks, with twice as many subjects receiving Imreg 1 as placebo. At the end of the 6 month period, subjects in both the placebo and Imreg I groups were offered Imreg I for up to 16 months. Subjects were not supposed to be receiving therapy to prevent opportunistic infections. In the first 6 months of the study, 1 subject on Imreg 1 developed PCP on the 21st day of the study. As subjects needed at least 4 weeks of Imreg 1 therapy for the drug to take effect, the data on him was excluded from the general analysis. In contrast, 3 subjects in the placebo arm developed opportunistic infections during the initial 6-month period. Measurements of quality of life during the trial showed that 47% of subjects on Imreg 1 "either returned to work or started to work with more energy," whereas only 16% of subjects on placebo did so. This difference was statistically significant, that is, not likely due to chance. At the start of the trial, the differences in CD4+ cell counts between the placebo group (307 cells) and the Imreg 1 group (383 cells) were not statistically significant. By the end of the first 6 months of the study, the CD4+ count of the Imreg 1 group had increased to an average of 429 cells, while the count in the placebo group fell to an average of 304 cells. This difference between the 2 groups was statistically significant. By the 12th and 18th months the differences in CD4+ cell counts were no longer statistically significant. All in all, Imreg l produced a decrease in progression to AIDS -- 2 of 34 subjects (6%), compared with 6 of 15 subjects on placebo (40%). According to the trial investigators, "the incidence of AIDS was 4 times lower in subjects [on Imreg 1] with CD4+ counts of less than 200 cells compared with the placebo". Imreg 1 is thought to provide benefits to subjects by interacting with key cells of the immune system located in the skin. In laboratory experiments, Imreg 1 has increased production of interferon and the T-cell growth factor interleukin 2. Imreg 1 appeared to cause side effects in only one subject, whose chronic hepatitis worsened with Imreg 1 injections. The drug is made by Imreg Inc., New Orleans, Louisiana. REFERENCES: 1. Fiala M, Cone LA and Sayre JW. Clinical benefits and recovery of delayed-type hypersensitivity in patients with AIDS-related complex treated with Imreg-1 or placebo. International Journal of Immunopharmacology 1991; 13(7): 999-1004. ***** B. Specific nutrients and HIV/AIDS The exact role vitamin, mineral, and other nutritional deficiencies play in disease progression among patients with HIV infection is uncertain. Research over the past several years has suggested that low levels of zinc may be associated with worsening immune deficiency. Another study has found that vitamin B6 supplements may, in certain patients, help raise CD4+ cell counts. Still other studies have found deficiencies of vitamins A, B1 B6, B12 E, and minerals. Precisely why some of these deficiencies occur is not known; perhaps the use of certain drugs cause an increased demand for nutrients. Such a relationship may exist between AZT and zinc. In other cases, reduced appetite caused by illness may result in poor eating habits, causing nutrient deficiencies. Scientists in Amsterdam have noted that changes in energy cycles and metabolism occur early, even when patients still have high CD4+ counts and are symptom-free. Other researchers, at the Institute of Immunology and Genetics (Heidelberg), as well as at the German Primate Centre (Gottingen), have observed that monkeys infected with SIV (Simian Immuno- deficiency Virus) develop disorders in their metabolism of amino acids. Thus, some of the nutritional deficits in people may arise as a result of HIV infection itself. In other cases, diarrhea and physical changes to the intestine likely also play a role. Physicians may wish to consider testing for nutritional deficiencies and recommending changes to their patients' nutritional support programmes. REFERENCES: 1. Raiten DJ. Nutrition and HIV infection: a review and evaluation of the extant knowledge of the relationship between nutrition and HIV infection. FDA contract No. 223-88-2124. November, 1990. 2. Coodley G. Nutritional deficiency and AIDS. Annals of Internal Medicine 1990;113(10): 807. 3. Boudes P, Zittoon J and Sobel A. Folate, vitamin B 12 and HIV infection. Lancet 1990;335: 1401-1402. 4. Hommes MJI, Romijin JA, Endert E and Sauerwein HP. Resting energy expenditure and substrate oxidation in Human Immunodeficiency Virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage. American Journal of Clinical Nutrition 1991;54: 311-315. 5. Eck H-P, Stahl-Herming C, Hunsmann G, and Droge W. Metabolic disorder as early consequence of simian immunodeficiency virus infection in rhesus macaques. Lancet 1991;338: 346-347. ***** C. Changes in zinc/copper ratios It is well known that some patients with advanced HIV infection develop various nutritional deficits over the course of their illness. During infection, blood levels of zinc decrease as the metal is needed by the liver. Simultaneously, blood levels of copper increase. There is evidence to suggest that both metals are important for immune function. Several studies have shown that more advanced HIV infection is associated with low blood levels of zinc, but the information on copper is not as consistent. Doctors at the University of Miami, and elsewhere in the USA, have carried out a study to determine if there is a relationship among zinc, copper, immune function and disease progression in people with HIV infection. Fifty-four subjects who were HIV-infected and showing signs of disease progression were matched with a group of 54 HIV-infected subjects whose condition appeared stable. Another group of 54 non-HIV-infected subjects was used as a control. The average length of follow-up was 2-1/2 years. The researchers found that of the three groups, it was the HIV-infected subjects who experienced disease progression who had the highest blood levels of copper. The HIV-positive non-progressors had the next highest level of copper, despite all 3 groups having similar dietary intake of copper and zinc. These differences were statistically significant. According to the study investigators, their research suggests that trends in blood levels of zinc and copper represent markers of disease progression. Cancer researchers have suggested that high blood levels of copper may also herald the onset of worsening disease. Some scientists think that supplementation with zinc may help in delaying disease progression for a number of reasons. Zinc plays a key role in many enzyme systems in the body, and the mineral is depleted by stress, infections, cancer, and sex Moreover, according to Canadian researchers, zinc is needed to activate an essential immune-boosting hormone in the body called thymulin, levels of which fall with increasing immunodeficiency. Others caution that zinc is required by HIV for replication, and zinc supplements may actually increase viral replication. One scientist pointed out that many nutrients in addition to zinc are needed for viral replication. He said that it is likely that long-term supplementation of high doses of zinc (more than 150 mg/ day) can cause immune suppression. Excess doses of any one nutrient are likely to put the rest out of balance. For instance, there is a complex interplay between zinc and copper in the body, and large doses of zinc can reduce blood levels of copper. Similarly, large doses of copper are thought to reduce blood levels of zinc. (Personal communication, Chester Myers, Ph.D.) . Some people alternate their zinc and copper supplementation on different days. Small, uncontrolled studies using zinc (50 to 100 mg/day) supplements for subjects with cancer, as well as for others with HIV infection, suggest that the mineral may have restored some immune functions and improved CD4/CD8 ratios. Until larger, long-term studies are performed, the best dose of zinc for people with HIV infection remains uncertain. REFERENCES: 1. Graharn NMH, Sorensen D, Odaka N et al. Relationship of serum copper and zinc levels to HIV-1 seropositivity and progression to AIDS. Journal of Acquired Immune Deficiency Syndromes 1991;4(10): 976-980. 2. Raiten DJ. Nutrition and HIV infection: a review and evaluation of the extant knowledge of the relationship between nutrition and HIV infection. Food and Drug Administration contract No. 223-88-2124. November, 1990. ***** D. Vitamin B6 and immune function Researchers in Florida enrolled 44 HIV-infected subjects for an investigation into the nutritional deficiencies which may occur in early HIV infection. Another group of 44 subjects without HIV infection was used as a control. All HIV-positive subjects were symptom-free and were not taking any anti-virals such as AZT, interferon, or ribavirin. Investigation of the diets of subjects found that all were eating "adequate" amounts of nutrients. Analysis of their blood samples found that approximately 1/3 of subjects with HIV infection had deficiencies of vitamin B6 statistically significant compared with control subjects. Although those with deficiencies were found to be consuming low levels of vitamin B6, the amounts found in their diets met the recommended daily allowance for that vitamin. Subjects with HIV infection taking supplements of 20 mg/day of vitamin B6 had normal blood levels of that vitamin. The researchers found that deficits in vitamin B6 appeared to be associated with defects in immunologic function among people with HIV infection. In those subjects with HIV infection taking more than 20 mg/day of vitamin B6, immunologic function was greater than in those subjects with HIV who were deficient in this vitamin. Why vitamin B6 deficiency occurs despite supposedly "adequate" intake is unclear. Perhaps physical changes to the intestine in patients as a result of HIV infection results in malabsorption. Reduced levels of stomach acid may also contribute to poor absorption of B6, and altered metabolism by the liver may be another cause, especially in chronic users of alcohol. As some patients with HIV have been found to have kidney dysfunction, loss of vitamin B6 through the kidneys may be another cause of low blood levels of this vitamin. That supplements of at least 20 mg/day corrected the vitamin B6 deficiency is reassuring. In related experiments, 12 HIV-infected subjects who were vitamin B6 deficient were given 20 to 25 mg/day of the vitamin. Eight of the 12 had average increases of 121 CD4+ cells over a 6-month period. Improvements in other immune functions were also noted. Although vitamin B6 deficiency is not the sole cause of immune dysfunction seen in people with AIDS, doctors may wish to consider testing for deficiency of this vitamin and recommend supplements if necessary. Some scientists caution that supplementation of just one B vitamin over long periods of time may cause deficiencies of the other B-vitamins; it is likely better to take more-or- less equal doses of all B-vitamins, as found in some B-complex formulations. (Personal communication, Chester Myers Ph.D). REFERENCES: 1. Bauln MK, Mantero-Atienza E, Shor-Posner G et al. Association of vitamin B6 status with parameters of immune function in early HIV-1 infection. Journal of Acquired Immuno Deficiency Syndromes 1991; 4(11): 1122-1132. 2. Mantero-Atienza E, Baum M, Beach R et al. Vitamin B6 and immune function in HIV infection. VII International Conference AIDS, San Francisco, 1990 abstract #3132. ***** E. Vitamin B12 and quality of life People with HIV infection can develop vitamin B12 deficiency, perhaps from poor diet, malabsorption, drug interactions, or intestinal infections. Researchers in the USA may have found what could be another cause of vitamin B12 deficiency, involving a substance called intrinsic factor (IF). For vitamin B12 to be absorbed from the intestine it must first bind to IF. The researchers studied 27 HIV-infected subjects, 14 of whom had low blood levels of vitamin B12 but normal levels of an associated B-vitamin, folic acid. All subjects had a form of red blood cell anemia (megaloblastic anemia). The 14 subjects with low blood levels of vitamin B,2 needed frequent intramuscular injections -- 2000 micrograms 3 times per week -- to prevent deficiency. What is so striking about this research is that a few days after an injection of the vitamin, blood levels of vitamin B12 would rise sharply, but within a few days would fall just as sharply. In some cases antibodies which attacked IF were found in subjects' blood. These antibodies are thought to play a major role in the development of vitamin B12 deficiency, not only in this group, but in many other people with HIV infection. In this study, repeated injections of vitamin B12 resulted in increased energy, a sense of well-being, and signs of decreased nerve damage. The study researchers suggested that patients with antibodies to IF may be helped by the use of very small doses of corticosteroids, thereby suppressing autoantibody formation. Such therapy has proved beneficial in other cases of vitamin B12 anemia associated with autoimmune disorders. Alternatively, antibody infusions, which are helpful in other cases of HIV- related autoimmunity, may also be of use for treating vitamin B12 deficiency. REFERENCES: 1. Harris PJ and Candeloro P. HIV-infected patients with vitamin B12 deficiency and autoantibodies to intrinsic factor: disease pathogenesis and therapy. AIDS Patient Care 1991;5(3): 125-128. ***** F. Folic acid and cervical cancer In the USA, cancer of the cervix is the 9th leading cause of death due to cancer among women. Every year, there are at least 50,000 cases of this cancer in the USA, and its incidence is even higher in developing countries. The evidence suggests that cervical cancer (cervical intraepithelial neoplasia or CIN) is associated with infection by certain strains of a virus called HPV (Human Papillomavirus). As women without CIN have been found to have the genetic material of HPV in their cervix, it is thought that co-factors may be involved in "activating" these cancer-causing genes. Data generated from studies suggest that nutrition, poverty, cigarette smoking, and immunity are all co- factors for CIN. Several research groups have found that vitamin deficiency may play a role in CIN. Interest has focused on the B-vitamin folic acid because a number of studies have reported that folic acid deficiency may be associated with CIN. Researchers at several sites in the USA have recently conducted a study of 464 women, who did not have HIV infection, for nutritional risk factors, particularly folic acid deficiency, in the development of CIN. The researchers measured the folic acid content inside red blood cells (RBCs) which is thought to provide a more accurate assessment of folic acid levels than measurements from blood. Levels of folic acid in the blood are affected by food intake, and thus fluctuate, whereas folic acid in RBCs is a better index of long-term nutritional status. The researchers found that folic acid deficiency by itself was not significantly associated with increased risk for CIN. In women who were deficient in folic acid and infected with HPV-16 there was a statistically-increased risk of CIN. This is not surprising, as a recent review of experimental work has suggested that folic acid deficiency by itself does not result in cancer. However, cells deficient in this B- vitamin are "more susceptible to the effect of known [cancer-causing chemicals]." This is supported by results from a 6-month study of oral supplementation of folic acid. In that study, folic acid -- in a dose of 5 mg/day -- seemed to reduce the incidence of abnormal cells in affected subjects but did not change the course of cancer. Supplementation with this vitamin appears to benefit subjects at high risk of other cancers as well. Women with HIV appear to be at increased risk of CIN. The immune suppression caused by HIV and HPV, combined with possible folic acid deficiency, may interact and create conditions favourable to the development of CIN. Regular pap smears and colposcopy may help detect abnormal cells before they spread. Perhaps supplements of folic acid for women with HIV who are at risk of CIN may decrease the occurrence of CIN. Given its low toxicity, low cost, and potential benefit, doctors may wish to consider adding folic acid to the treatment regimen for women with HIV infection. REFERENCES: 1. Butterworth CE, Hatch KD, Malcaluso M et al. Folate deficiency and cervical dysplasia. Journal of the American Medical Association 1992; 267(4): 528-533. 2. Chopra V and Tyring S. Suppression of Interleukin-2 production and activity by factor(s) released by peripheral blood mononuclear cells during Papillomavirus infections Viral Immunology 1991: 4(4): 237-247. ***** G. Helpful sugar from yeast Several immune boosters have extracts of bacteria as a major ingredient. One immune booster under investigation is the sugar glucan. First isolated from yeast in the 1940s, glucan appears to be beneficial in the treatment of infections in laboratory experiments with animals. That glucan, a sugar, can do this is not entirely surprising as other, more complex sugars such as Lentinan and Krestin (both licensed in Japan) also have immune- boosting properties. In order to make glucan safer for intravenous use, researchers have made it water-soluble and added sulphur, forming glucan sulphate. The exact mechanism whereby glucan sulphate exerts its immune-boosting activity, like many similar drugs', is not fully understood. Results from laboratory experiments suggest that glucan sulphate interacts with cells of the immune system known as macrophages, "enhancing their number and function". In experiments with mice, it also appears to significantly improve bone marrow function, significantly increasing survival. "Preventative therapy" with glucan sulphate before infection also resulted in increased survival. Preliminary experiments on humans with glucan suggest an immune-boosting effect. Immunotherapy with glucan sulphate may have several advantages, as glucans have been shown to have anticancer, anti- bacterial, and anti-fungal activity. The sugar also appears to work with chemotherapy, and relieve immune suppression. Moreover, sulphated glucan, like sulphated dextran, sulphated amphotericin B, and several other compounds, may also have anti- HIV activity. The researchers recommend further testing of glucans. REFERENCES: 1. Williams DL, Pretus HA, McNanee RB et al. Development, physiochemical characterization and preclinical efficacy evaluation of a water soluble glucan sulfate derived from Saccharomyces cerevisiae. Immunopharmacology 1991;22: 139-156. ***** H. Friendly yeast for diarrhea? The cause of life-threatening diarrhea seen in advanced HIV infection is not always clear. Possible origins may include a variety of disease- causing organisms, cancer, and even nerve destruction. Researchers in Lyon, France, have used a yeast, Saccharomyces boulardii, for the treatment of AIDS-related diarrhea. Thirty subjects with a history of CMV, MAC, and Kaposi's sarcoma were experiencing severe diarrhea, excreting "4 to 8 litres of watery stool per day for at least 3 months." Experiments with at least 4 anti-diarrheal agents in the past were unsuccessful. Repeated examinations of stool samples could not identify disease-causing organisms. Given 3 grams/day of the yeast, most patients found their diarrhea decreased within 48 hours and was gone 8 days after beginning the yeast treatment. Anecdotal reports from Toronto indicate that use of this yeast has helped some patients, though it may take up to a week before diarrhea stops. How the yeast provides this beneficial effect is not fully understood. It is thought that S. boulardii may release chemicals, such as lactic acid, which are harmful to other micro-organisms (Personal communication, Chester Myers Ph.D.) . Perhaps some of the chemicals released, such as glucan, may have an effect on the local immune system of the bowel and large intestine which helped the body to overcome the diarrhea. S. boulardii is usually considered more "friendly" than most other yeasts. Faced with a patient experiencing severe diarrhea unresponsive to standard treatment, doctors may wish to consider short-term use of Saccharomyces boulardii. Capsules of this yeast are available from selected health food stores in Canada. REFERENCES: 1. Saint-Marc T, Sellem C, Rosellu L et al. Treatment of chronic diarrhea with Saccharomyces Boulardii. VI International Conference AIDS, San Francisco, 1990, Poster THB 363. ***** III. INFECTION FIGHTERS A. Sparfloxacin for MAC and TB Recently, outbreaks of TB resistant to conventional anti-TB therapy have been reported. As well, no new effective drugs against MAC (Mycobacterium Avium Complex) have been licensed in North America, although clarithromycin and azithromycin look promising. As yet, the optimal drug, or combinations of drugs, for prophylaxis or prevention of MAC is uncertain. The drug rifabutin, in doses of 300 to 600 mg/day, may delay the onset of MAC, according to preliminary results from a controlled trial in the USA. Experience with MAC and TB suggests that it is easier for these mycobacteria to develop resistance to one drug alone than to several agents together. One relatively new agent which may be of use against MAC/ TB is the antibiotic sparfloxacin. Developed in Japan in the last decade, sparfloxacin is currently undergoing testing in North America and the European Community for use against TB and MAC infections. In experiments with TB and MAC conducted at the Institut Pasteur (Paris) researchers have found that concentrations of sparfloxacin which kill bacteria can be achieved with oral use. In one experiment, sparfloxacin was superior to ofloxacin and ciprofloxacin in its anti-TB activity. One of the reasons that infection with mycobacteria such as MAC are difficult to treat is their relatively thick cell wall, which impairs the entry of antibiotics inside the organism. Second, MAC has developed resistance to combinations of several antibiotics. Third, MAC often infects macrophages, cells of the immune system, which are critical for controlling infections. Once inside a macrophage, MAC gets additional protection from antibiotics, as these drugs do not usually penetrate macrophages well. The infected macrophage often becomes dysfunctional as a result of MAC infection and further control of the parasite is hampered. A large research team at the Institut Pasteur is studying ways to overcome these problems. For instance. they were among the first to show that the new antibiotic clarithromycin was effective in killing MAC. They have shown that in experiments with macrophages and MAC, sparfloxacin was effective against the mycobacteria. They also used the drug ethambutol in their experiment. Ethambutol may be a critical component of anti-MAC therapy because it has the ability to break the cell wall of MAC and allow the entry of other more potent antibiotics and the increased killing of mycobacteria. Based on the results of the French experiments, potential anti-MAC combinations for testing in humans could be sparfloxacin and ethambutol, and sparfloxacin with rifampin and clarithromycin. The researchers emphasized that these laboratory results need to be confirmed with experiments on humans. Researchers at the University of Tokyo have been conducting experiments on humans in an attempt to determine the relationship between oral doses of sparfloxacin and the resulting concentration of the drug in blood and tissues. Using 100 and 200 mg doses, the doctors found that a single 200 mg oral dose resulted in higher blood levels than the 100 mg dose. After the 200 mg dose, blood levels of sparfloxacin peaked 5 hours after taking the drug. A comparison of the Japanese data with those from the Institut Pasteur suggests that concentrations achieved with oral use should be able to inhibit the growth of MAC. As sparfloxacin remains in the blood for a prolonged period of time, perhaps the antibiotic may need to be taken only a few times per day. Clinical trials using sparfloxacin are underway at several sites in the USA. REFERENCES 1. Rastogi N and Goh KS Invitro activity of the new difluorinated quinolone sparfloxacin (AT4140) against Mycobacterium tuberculosis compared with activities of ofloxacin and ciprofloxacin. Antimicrobial Agents and Chemotherapy 1991;35(9): 1932-1936. 2. Rastogi N, Labrousse V, Goh KS and De Sousa JPC Antimycobacterial spectrum of sparfloxacin and its activities alone and in association with other drugs against mycobacterium avium complex growing extracellularly and intracellularly in murine and human macrophages Antimicrobial Agents and Chemotherapy 1991;35(12): 2473-2480 3. Nogita T and Ishibashi Y. The penetration of sparfloxacin into human plasma and skin tissues Journal of Antimicrobial Chemotherapy 1991;28(2) 313-314. ***** IV TESTING A. Colposcopy study raises questions about pap smears Due to their suppressed immune systems, women with HIV infection are at increased risk of developing of cervical cancer. Researchers in New York have performed a study on 32 HIV-positive women to look at the relationship between immune function and the appearance of cervical cancer or CIN (cervical intraepithelial neoplasia). Five of the 32 women had AIDS and 16 received AZT. One woman had cervical cancer and 4 had yeast infections (vaginal). Twenty-five, or 78% of the group of 32, had normal pap smears. When colposcopies were performed, 13 of the group were found to have CIN. In addition, 14 other women had inflammations of the cervix, with one woman having both CIN and cervicitis. Of the entire group of 32 subjects, only 5 were found to have non-cancerous growths when colposcopies were performed. All 5 subjects with AIDS had CIN, compared to 8 cases of CIN in 27 non-AIDS HIV-positive women. Subjects with AIDS and CIN had lower CD4/CD8 ratios and lower average CD4+ cell counts than the subjects without AIDS. Use of AZT did not appear to have a major effect on the development of CIN. According to the study researchers, "the most significant finding in our study was the 41% rate of histologically confirmed CIN in our HIV- positive study group. The majority of patients reported previously normal pap smears, and only one had a history of an abnormal smear performed after her HIV diagnosis was made." The researchers add, "Based on our findings, we urge extreme caution in assuming normal histology from a normal Pap smear in the HIV-positive woman." One potential treatment which has worked for other non-HIV-infected but immune-suppressed women is the use of the drug 5-fluorouracil directly on to lesions. Vitamin A compounds such as Retin-A and Accutane may also help. REFERENCES 1. Maiman M, Tamicone N, Viera J et al. Colposocopic evaluation of Human Immunodeficiency Virus-seropositive women. Obstetrics and Gynecology 1991;78(1): 84-88. ***** SUBSCRIPTION FEES TreatmentUpdate (TU) and TraitementSida (TS) are published by the Community AIDS Treatment Information Exchange (CATIE) and are available to the public on the basis of a sliding scale of subscription fees. Standard fees have been set for individuals and institutions and the scale slides upwards or downwards according to financial situation. For those who cannot afford to pay fee is waived. ONE-YEAR SUBSCRIPTION RATE WITHIN CANADA 1. Individuals (TU or TS) $ 15 2. Individuals (TU and TS) $ 20 3. Institutions (TU or TS) $ 25 4. Institutions (TU and TS) $ 30 5. Back issues (all requests), each $ 1.50 FOR SUBSCRIPTION OUTSIDE CANADA, PLEASE PAY IN U. S. DOLLARS Send cheque or money order payable to CATIE to: CATIE 517 College Street, Ste 324 Toronto, Ontario Canada M6G 4A2 DISCLAIMER Community AIDS Treatment Information Exchange (CATIE) publishes TreatmentUpdate/Traitement/Sida as an informational resource for individuals considering experimental treatments and/or therapies for AIDS and HIV related illnesses. Persons' Living With AIDS and HIV as well as their medical advisors must recognize that treatment issues relating to HIV and AIDS are complex and that information regarding treatments and therapies may change from day to day. Individual's should gather as much information as possible concerning a particular therapy, experimental treatment or combination of treatments before making a decision whether or not to use such treatment(s). Such decisions should always be made in consultation with a physician who is knowledgeable about AIDS. HIV-related illnesses and the treatment(s) or therapies in question. CATIE does not recommend, advocate, or endorse the use of any particular treatment(s) or therapy described in Treatment/Update/TraitementSida. CATIE therefore does not accept the risk of, or responsibility for, any damages, costs, or consequences of any kind whatsoever which may arise or result, either from use or reliance on the information contained herein, or due to any errors contained herein. Persons relying on the information contained in this publication must do so at their own risk. TREATMENT UPDATE 29 Copy editing: Alan Stewart Desktop Publishing: Alex Berry, Sean Hosein Distribution: Bill Naumovich, Jack Reynolds, Harry Collie, John Guenther Editor: Sean Hosein Production Manager: Alex Berry Subscriptions: Jack Reynolds Copyright (c) Sean Hosein, 1991 &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display