TreatmentUpdate 53 ------------------ Community AIDS Treatment Information Exchange, Vol. 5, No. 4 October 1994 - ISSN 11817186 ------------------------------------------------------------ TABLE OF CONTENTS I ANTI-HIV AGENTS A. Cystamine--a new antiviral? ********** I ANTI-HIV AGENTS A. Cystamine--a new antiviral? Background Most anti-HIV drugs (AZT, ddC, ddI, d4T) can block HIV from infecting uninfected cells. These drugs do not significantly reduce the production of virus from cells already infected by HIV. Drug companies are testing many other compounds to find better anti-HIV agents. One potential anti-HIV agent is cystamine. Researchers in Italy have performed lab experiments using cystamine, HIV and infected cells. Results from their work suggests that cystamine can block HIV-infected cells from producing new viruses. Results from the Lab Small concentrations of cystamine were able to reduce or block production of HIV from newly infected cells including T-cells and macrophages. As well, cystamine also reduced production of HIV from cells that had been infected for several weeks. An Assembly Line Destroyed The research team testing cystamine were not sure why the drug could stop production of HIV. Cells of the immune system treated with cystamine did not produce ale natural antiviral substance interferon. Nor did the drug damage certain enzymes that HIV needs. An infected cell producing HIV is similar to an assembly line. Different parts are brought together at various times with lie final product being new HIV ready to infect other cells. By means of several tests the researchers found that cystamine damaged the virus assembly line. Instead of producing dangerous virus, lie cystamine-treated cells produced copies of HIV that were 'defective'. These copies of lie virus often had parts missing. In all of the experiments with HIV-infected cells, cystamine had much greater antiviral effect(s) than AZT. A Drug Given to Children Other researchers have used cystamine on mice and rats without causing toxicity. Perhaps more importantly, researchers gave a compound 'related' to cystamine, cysteamine, to children with kidney damage without causing toxicity. These children had cells that could not move/exchange the amino acid cystine. Levels of cystine then build up forming crystals that damage the kidney and eventually other organs. Treatment with cysteamine protected them from kidney damage. Current Use The Food and Drug Administration (FDA, USA) has granted a Treatment IND (Investigational new drug) to Dr. Jes Thoene at the University of Michigan. This treatment IND is used only for children whose kidneys are damaged by cystine build up. Sigma Chemical, St. Louis, USA, makes the drug (in the form of cysteamine hydrochloride). The children receive "50 to 60" mg per kilogram of body weight every six hours. In the past 7 years patients could also receive the drug phosphocysteamine made by Medea Labs, Port Jefferson Station, New York. This other form of cysteamine could be taken in doses of 1.3 to 1.95 mg per square metre of skin every day. At these doses the drugs did not cause toxicity in any of the children, but it is not clear which dose might be best for HIV-infected adults or children until clinical trials are performed. References: 1. Bergamini A, Capozzi M, Ghibelli et al. Cystamine potently suppresses in vitro HIV replication in acutely and chronically infected human cells. Journal of Clinical Investigation 1994;93:2251-2257. 2. Markello TC, Bernardini M and Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. New England Journal of Medicine 1993,328 (16):1157-1162. II INFECTION FIGHTERS A. PCP - experimental combinations Background In North America the life-threatening pneumonia PCP is still a common cause of death for patients with AIDS. Doctors can choose several antibiotics with which to treat PCP: * pentamidine (intravenous) * Bactrim/Septra * clindamycin-primaquine * Mepron (atovaquone) * dapsone-trimethoprim * trimetrexate-dapsone Side Effects These antibiotics can cause side effects in some patients. For some the side effects are minor and can be ignored but for others side effects can be severe especially if patients are allergic to sulfa drugs. Drug companies are testing many antibiotics to find less toxic treatments. Researchers at Abbott Laboratories (Illinois, USA) have been weakening the immune systems of rats causing them to develop PCP. The researchers then tested a number of antibiotics to observe their anti-PCP effects. Erythromycin and Relatives In 1989 German doctors reported that 2 to 3 g/day of the antibiotic erythromycin was an effective therapy for patients (HIV-infected) wit PCP. Since then two antibiotics 'related' to erythromycin--azithromycin and clarithromycin have been licensed (for infections other than PCP). Some doctors treating patients with HIV/AIDS have used these two 'new' antibiotics in combination with other drugs to treat the life-threatening brain infection 'toxo' (toxoplasmosis) and MAC infection. Antibiotics Technicians at Abbott Laboratories gave rats steroids to weaken their immune systems and then infected them with the microbe that causes PCP. Some rats received antibiotics while others did not. The researchers used: * Bactrim/Septra * pentamidine * sulfamethoxazole * clarithromycin While each of the antibiotics could reduce the severity of PCP, combinations of clarithromycin (a drug licensed to Abbott Labs) and sulfamethoxazole produced better results. Using the drugs together also seemed to increase the concentration of clarithromycin in the lungs and blood. From Rats to Humans While the scientists tested several doses of sulfamethoxazole, not all of them can be used in humans. Doctors prescribe clarithromycin in doses of 1 to 2 grams daily when treating MAC infection. Many patients with AIDS cannot tolerate sulfa drugs so a combination of clarithromycin and sulfa would not be practical. References: 1. Dorlemann A, Reisinger E, Schwander S. et al. Erythromycin in the treatment of PCP in AIDS patients. V International Conference on AIDS, Montreal, Canada June 4-9, 1989, abstract TBP 39, page 293. 2. Alder J. Mitten, Shipkowitz N. et al. Treatment of experimental Pneumocystis carinii infection by combination of clarithromycin and sulfamethoxazole. Journal of Antimicrobial Agents and Chemotherapy 1994;33:253-263. 3. Smith GH. Treatment of infections in the patient with Acquired Immunodeficiency Syndrome. Archives of Internal Medicine 1994;154:949-973. B. Vitamin C and the common cold Background In Ontario, people with HIV/AIDS who can afford to buy nutritional supplements often do so (E Mykhalovskiy, personal communication). Some buy multivitamin/mineral supplements, others may have more detailed regimens and use extra protein, fatty acids, coenzyme Q10 and carnitine among other supplements. In a disease where malabsorption, diarrhea and altered energy cycles (and poor eating habits) may be common, it may not be surprising that patients buy these products. One common supplement is vitamin C. Vitamin C and HIV Several years ago researchers reported that vitamin C could block production of HIV in laboratory experiments with cells. To achieve this concentration in the body humans would have to take minimum of 12 g/day of this vitamin. While many compounds can block HIV infection in the lab, they do not always provide benefit to patients with HIV/AIDS. Some patients and doctors who care for them find that extra vitamin C may help them recover from certain infections faster. One infection where vitamin C has been tested in humans is the common cold. Vitamin C--Prevention Against The Common Cold? Every year infection from the common cold affects millions of people. Over 20 research teams have tested vitamin C as a preventative against the common cold. Overall, the vitamin did not appear to be effective as a preventative. In one study using Canadian military personnel, the vitamin clearly protected them from the common cold. It appears that people in these studies needed at least 3 grams a day to receive benefit. Vitamin C--Reducing Symptoms Data from the 21 studies suggest that vitamin C can reduce the "severity of symptoms", or the amount of time patients had the cold. Twenty of these studies were double-blind studies (neither patients nor doctors knew what patients received; vitamin C or a dummy pill) and in some the decrease in symptoms was statistically significant. Vitamin C Doses In analyzing data from the studies it is hard to say which dose of vitamin C was fee most effective. "Most of the studies [used] 1 g/day increasing it to 4 grams when symptoms appeared while others took 6 g/day." One doctor gave patients as much vitamin C as they could tolerate until they developed 'bowel tolerance' or diarrhea. Dr. Cathcart found that 'healthy' patients can get diarrhea when they take between 4 and 15 grams/day of vitamin C. In comparison sick patients could tolerate up to 30 grams/day without diarrhea. How It Might Work Researchers are not sure how or why high doses of vitamin C could have reduced symptoms of the common cold. The immune system appears to need more vitamin C when people have the common cold and additional vitamin C may fill this need. The vitamin also protects cells from damage by highly active compounds called 'free radicals'. While patients have the cold their bodies may produce higher-than-normal levels of 'free radicals' and vitamin C may provide some protection. Doctors may wish to keep these results in mind when treating patients with the common cold. Further details about vitamin C appear in Treatment Update 13 and 18. References: 1. Hemila A. Does vitamin C alleviate the symptoms of the common cold? A review of current evidence. Scandinavian Journal of Infectious Diseases 1994;26:1-6. C. Protecting eyes from CMV Background The sight-threatening eye infection CMV retinitis is a common problem for people wit AIDS in North America. Patients with AIDS who may be at high risk for this complication are those with less than 100 CD4+ cells, particularly those with less than 50 CD4+ cells. Usually there are no early wag signs of retinitis and patients may not suspect that they have it until some damage has occurred. Regular eye exams by an ophthalmologist are the only way retinitis can be detected if the patent has no symptoms or normal vision. Some patients may notice 'floaters' or cotton wool spots across their eyes. Having floaters alone does not necessarily mean that the patient has retinitis. Treatment Ganciclovir (Cytovene, DHPG) is often the drug that doctors first prescribe for CMV-retinitis. Initially patients may receive: * 5 mg/kg of body weight/12 hours for 10 to 14 days Once the infection has stopped spreading patients receive maintenance therapy: * 5 mg/kg/day for between 5 and 7 days. Some doctors may use a Monday, Wednesday, Friday schedule. Ganciclovir does not destroy CMV; the drug stops CMV-infected cells from producing virus. Eventually CMV becomes resistant to the effects of ganciclovir and the retinitis worsens and patients can lose their vision. Foscarnet (Foscavir(R), Sodium Phosphonoformate) Doctors may switch patients from ganciclovir to foscarnet. In one controlled study, 234 subjects received either ganciclovir or foscarnet. Subjects who received foscarnet lived, on average, 4 months longer than subjects receiving ganciclovir. This difference was statistically significant. Subjects receiving foscarnet who had kidneys that were not working normally did not have extended survival. Initially, doctors often prescribe foscarnet 60 mg/kg for 1 hour every 8 hours for 2 or 3 weeks. As well, some doctors suggest that an infusion of salt solution (1 litre) during therapy reduces the toxicity of foscarnet to the kidneys. For maintenance therapy doctors may prescribe 90 to 120 mg/kg/day. Some doctors are experimenting with different schedules such as Monday, Wednesday, Friday; others recommend Monday through Friday. Few Choices Eventually the protection of foscarnet will fade. Some researchers think that not enough foscarnet or ganciclovir enters the eye and this is why the virus quickly becomes resistant to those drugs. To preserve vision some doctors and their patients are experimenting with different regimens, drugs, and new ways to deliver drugs to the eyes. Here are some examples: * combination therapy with ganciclovir and foscarnet * alternating treatment with ganciclovir or foscarnet * pellets of slow-release ganciclovir in the eye * gene therapy * new antiviral drugs such as HPWC * new foams of old drugs such as Valaciclovir In this issue of TreatmentUpdate/TraitementSida we report on some of these drugs and over reports on potential CMV therapies will appear in future issues. As we go to press we do not have details about the effectiveness of gene therapy. References: 1. Smith GH. Treatment of infections in the patent with Acquired Immunodeficiency Syndrome. Archives of Internal Medicine 1994;154:949-972 2. Kupperman B, Quiceno JL, Flores-Aguilar M, et al. Intravitreal ganciclovir concentrations after intravenous administration in patients with cytomegalovirus-retinitis; implications for therapy. Journal of Infectious Diseases 1993;168:1506-1509. 3. Polis M, De Smet M, Baird BE, et al. Increased Survival in a cohort of patients with Acquired Immunodeficiency Syndrome and CMV retinitis who received sodium phosphonoformate. American Journal of Medicine 1993;94:175-180. D. Combination treatment for CMV eye infections Background Although the drugs ganciclovir and foscarnet can block infection and damage from CMV, these drugs do not destroy the virus. Eventually patients treated with these drugs have outbreaks of retinitis. In some cases patients can have worsening symptoms in as little as 3 months after starting maintenance therapy. As there are no widely available alternatives, doctors are experimenting with combinations of both drugs. Treatment and Maintenance Doctors at the University of California-Davis recruited 9 subjects (8 males, 1 female) with CMV retinitis into their study. At first these subjects received ganciclovir intravenously 5 mg/kg/12 hours for between 2 and 4 weeks until they had reduced symptoms (3 of the subjects also received oral ganciclovir but doctors did not provide further details). Alternatively, doctors prescribed foscarnet for some patients 60 mg three times daily for between 2 and 4 weeks until symptoms resolved. At that point doctors then gave them maintenance therapy. Subjects on foscarnet maintenance therapy received either 90 or 120 mg/kg/ day. Subjects on ganciclovir maintenance therapy received 5 mg/kg/day of that drug. Combinations for Relapse When subjects had worsening symptoms doctors gave them combination treatment: * ganciclovir 5 mg/kg twice daily and foscarnet 60 mg/kg 3 times daily for between 2 and 4 weeks. Once the infection was stopped then doctors prescribed one of two combination maintenance regimens: * low-dose; ganciclovir 5 mg/kg/day and foscarnet 90 mg/kg/day * high-dose; ganciclovir 5 mg/kg twice daily and foscarnet 120 mg/kg/day Did It Work? Recovery from eye damage varied. Seven subjects had "complete healing in both eyes", while others had complete healing in one eye and partial healing in the other. The 2 subjects with partial healing did not take their drugs as directed by the doctors. Doses and Recovery All 14 subjects who had 'complete' healing in their eyes received high-dose treatment and maintenance therapy. According to the study doctors, subjects did not have serious side effects. As well, subjects did not receive an infusion of one drug immediately after the other because of potential toxicity. Survival and Persistence Eventually most subjects died. About 1/2 the subjects lived for 1 year after doctors diagnosed CMV retinitis; the study lasted for about 1 year. According to be study doctors, "[subjects]...must be [very committed] to this [therapy because of the time involved--5 hours daily initially and then 3 hours during maintenance. Larger studies looking at combination treatment and maintenance therapy are underway in the USA. References: 1. Kupperman BD, Flores-Aguilar M, Quiceno JL at al. Combination ganciclovir and foscarnet in the treatment of clinically resistant cytomegalovirus retinitis in patients with Acquired Immunodeficiency Syndrome. Archives of Ophthalmology 1993;1 11:1359-1366. E. Alternating treatments for CMV to avoid resistance Background Infection of the eye by CMV (cytomegalovirus) can cause a variety of problems including the sight-threatening problem, CMV retinitis. Although ganciclovir and foscarnet can, for a time, stop further eye damage, they do not destroy the virus but simply block infected cells from producing more virus. Eventually the virus can tolerate the effects of these drugs and eyesight is threatened. There are few alternatives left for patients to use. To reduce the chances of CMV becoming resistant to ganciclovir and foscarnet doctors in Berlin are experimenting with a new schedule for maintenance therapy. Maintenance Doctors in Berlin enrolled 11 male subjects with AIDS in their pilot study. All subjects had CMV infection in various places, including the stomach, eyes, brain and throat. At least half of the subjects had a CD4+ cell count of 20 cells. Researchers did not provide details on CD8+ cell counts. Six subjects received a combination of ganciclovir 5 mg/kg "twice daily" as well as 60 mg/kg of foscarnet "3 times daily" for 3 weeks. The remaining 5 subjects received ganciclovir 5 mg/kg/day. All subjects received "maintenance therapy": "ganciclovir 5 mg/kg every other day alternating with foscarnet 120 mg/kg every other day." At least half of the subjects received maintenance therapy for 5 months. Results--Symptoms, Survival and Toxicity Half of the subjects did not have any worsening symptoms of CMV infection for 15 weeks once they started maintenance therapy. During maintenance therapy common side effects included "nausea and vomiting." The researchers think that these side effects were caused by foscarnet. By the 5th month of therapy 1/2 the subjects died and later a total of 9 subjects were dead. Four subjects died from complications due to CMV. One subject tolerated maintenance therapy for nearly 1 year and 3 others for more than 6 months. According to the researchers, larger trials of this combination should provide answers about the effectiveness of combination therapy versus 1-drug therapy (mono-therapy) for maintenance therapy. REFERENCES: 1. Peters M, Schrmann D, Bergmann F. et al. Safety of alternating ganciclovir and foscarnet maintenance therapy in Human Immunodeficiency Virus (HIV) -related cytomegalovirus infection: an open-label pilot study. Scandinavian Journal of Infectious Diseases 1994;26:49-54. F. Acyclovir plus Background Herpes viruses are a group of viruses including: * HSV-1 and -2 herpes simplex virus 1 and 2) These viruses can causes lesions/sores, eye and brain infection. * CMV (cytomegalovirus) This virus call cause the sight-threatening infection CMV retinitis, infection of the brain, bone marrow and intestine. * EBV (Epstein-Barr virus) * VZV (varicella Zoster virus) These virus can cause shingles and patients may have fever, chills, fatigue, muscle and joint pain. Doctors can prescribe the anti-herpes drug acyclovir (Zovirax(R)) to treat sores caused by HSV. Once the patient recovers, they may take lower doses of acyclovir to suppress the appearance of sores. The problem with taking continuous doses of the drug is that the virus will become resistant to acyclovir. At first doctors may raise the dose of acyclovir and this will probably help patients. Eventually the virus becomes resistant to even high doses of acyclovir (4,000 mg/day). At this point doctors may prescribe any one of the following drugs intravenously: * acyclovir S to 10 mg/kg/day * foscarnet 60 mg/kg once or more daily * ganciclovir S mg/kg/day * vindarabine 15 mg/kg/day In cases where the lesions are on the skin sometimes covering the skin with gauze wet with trifluridine (Viroptic(R)) can help. Note: For women with sores on their external genitals, Viroptic may not be as effective as in men. Unfortunately doctors are reporting more cases of herpes infections that are not only resistant to oral ganciclovir but to foscarnet and other drugs. Acyclovir When swallowed, only about 20% of acyclovir gets absorbed. To increase blood levels of acyclovir physicians may order intravenous acyclovir. This is not convenient for patients and eventually the virus may become resistant to even this. Some Patients with AIDS are taking up to 4 grams/day of acyclovir to delay the sight-threatening infection CMV retinitis. Researchers have not proven that this dose of oral acyclovir can delay this complication. Some researchers think that increasing the concentration of acyclovir inside the body may delay serious herpes virus infections. One way to increase blood levels of acyclovir (other than intravenous acyclovir) may be to take the related compound valaciclovir. REFERENCES: 1. Safrin S. Kemmerly S. Plotkin B. et al. Foscarnet-resistant herpes simplex virus infection in patients with AIDS. Journal of Infectious Diseases 1994;169;193-196. 2. Smith GH. Treatment of infections in the patient with Acquired Immunodeficiency Syndrome. Archives of Internal Medicine 1994;154:949-972. 3. Balfur HH, Benson C, Braun J. et al. Management of acyclovir resistant herpes simplex and varicella-Zoster vans infections. Journal of Acquired Immunodeficiency Syndromes 1994;7:254260. G. Varicella-zoster(R) for herpes viruses? Background In North America and Australia some patients with AIDS are using high doses (3.2 to 4 g/day) acyclovir to suppress or delay the appearance of: * lesions caused by HSV * the sight-threatening complication CMV retinitis Only about 20% of oral acyclovir gets absorbed when patients swallow the drug. Although intravenous acyclovir can increase blood levels of acyclovir higher than oral acyclovir, it is not convenient. One way to get greater concentrations of acyclovir in the body is to take a closely related product, valaciclovir (Varicella-zoster, BW256U87). Study Details Researchers in the USA enrolled 14 men and 3 women with AIDS into this study of Varicella-zoster. No subject had any life-threatening infection/cancer and half of them had a CD4+ cell count of 44 cells. Subjects were not supposed to enter the study if they had "severe or persistent nausea or diarrhea". Researchers gave subjects one of 2 daily doses of valaciclovir; 1,000 or 2,000 mg, both four times daily for 30 days. The drug came in 250 mg white capsules. Results--Absorption/Concentration The researchers found that subjects absorbed valaciclovir rapidly. The liver and intestines quickly converted valaciclovir into acyclovir. Within 15 minutes after swallowing a dose of the drug, technicians could detect acyclovir from blood samples. Subjects taking the 2,000 mg 4 times daily had higher blood levels of acyclovir than did subjects taking 1,000 mg 4 times daily. According to the researchers, blood levels of acyclovir were "5 tunes greater than those [seen] after [high-dose] acyclovir (4,000 mg/day)." For the subjects in the high-dose Varicella-zoster group, blood levels of acyclovir were similar to those seen in subjects receiving 5 mg/ kg every 8 hours. This is important because in one study researchers found that intravenous acyclovir seemed to delay the spread of CMV-retinitis. Toxicity About 1/3 of subjects had one or more of: * nausea * vomiting * diarrhea At high doses (2,000 mg/4 times daily) valaciclovir may affect the bone marrow reducing levels of white blood cells called neutrophils. These cells play an important role in defending the body from infections. Subjects whose blood levels of neutrophils fell while taking Valtex had them return to normal once they stopped taking the drug. But Will It Work? The high concentration of acyclovir in the subjects given Varicella-zoster is encouraging. Doctors in Canada and the USA (ACTG 204) are conducting a study testing: * low-dose acyclovir, 1600 mg/day * high-dose acyclovir, 3,200 mg/day versus * Valtex 2,000 mg/4 times daily to compare which is best at delaying the sight-threatening infection CMV retinitis in subjects with less than 100 CD4+ cells. Varicella-zoster is made by Burroughs Wellcome. References: 1. Jacobsen MA, Gallant J. Wong LH, et al. Phase I trial of valaciclovir, the L-Valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease. Antimicrobial Agents and Chemotherapy 1994;38(7);1543-1540 2. Jacobson MA. Valaciclovir (BW256U87): the L-Valyl ester of acyclovir. Journal of Medical Virology 1993; (supplement 1):150-153. H. Controlling yeast infections naturally Background Fungal infections by Candida in the skin, mouth and vagina are common in patients with HIV/AIDS. For some people these infections are minor, in others, serious. Other fungi attack the brain and lungs. Guidelines for the treatment of various fungal infections produced by the British Society for Antifungal Therapy appear in TreatmentUpdate 38. Why Yeasts? Yeast infections are common for at least 2 reasons * a weakened immune system * long-term use of antibiotics Humans have 'friendly' bacteria living in their mouths and intestines. These 'gut bugs' feed on milk sugar and produce vitamins which we absorb. Friendly bacteria also physically occupy space in our intestines This occupation (or colonization) of space by friendly bacteria prevents other microbes from growing. As well, friendly bacteria make chemicals which prevent fungi from growing out of control. Under normal conditions humans also have a small amount of Candida in their intestines. Helping Yeast The normal balance of microbes in the body can change because of * stress * use of antibiotics (they kill friendly bacteria) * diets high in sugar (which help yeast grow) * drugs that suppress the immune system (corticosteroids) * chemicals produced by yeast which suppress the immune system Risks and Benefits For most people simply using antifungal drugs will stop the fungus from spreading. Patients with HIV/ AIDS will probably still need to take antifungal drugs after the infection has been treated so that they do not 'relapse'. For these patients intermittent (such as Monday, Wednesday, Friday) or reduced doses of an antifungal drug are a typical maintenance strategy. Doctors and their patients will need to weigh the risks of long-term use of antifungals (drug-resistant yeast, potential toxicity to the immune system) against the benefits (clearance of infections, improved quality of life). Changes to the Diet Researchers experimenting on mice with damaged immune systems have made some interesting discoveries that may help some people with HIV/AIDS. It appears that sugar encourages the growth of yeasts. As well, we have heard reports from several doctors and their patients that eating less sugar has helped them reduce outbreaks of yeast infections. Substitutes For some people simply reading the list of ingredients of processed food that they buy is a good way to begin learning about the sugar in their diet. Sugar may be 'disguised' from the ordinary shopper as * corn and maple syrup * fructose * glucose * grape or raisin juice * invert sugar * sucrose Some people replace these forms of sugar with * barley malt extracts (which have complex carbohydrates but still taste sweet) * concentrated apple and pear juices to sweeten the taste of baked foods * Nutrasweet(R) (aspartame) Others add soluble fibre (found in apples, bananas, barley, carrots, citrus fruits, oats) to their diet. As well, some people eat yogurt and take capsules of friendly bacteria because yogurt may not have * friendly bacteria that are alive * strains of bacteria such as Lactobacillus bifidus or Lactobacillus acidophilus that are good at colonizing the intestines These patients and their doctors 'save' their antifungal drugs for when they have an outbreak of oral/vaginal fungal infections or take them intermittently 1 or 3 days a week. These courses of action may delay the appearance of drug-resistant fungus. References: 1. Vargus SL, Patrick CC, Ayers G and Huges WT. Modulating effect of dietary carbohydrate supplement on Candida albicans colonization and invasion in a neutropenic mouse model. Infection and Immunity 1993;61:619-626. 2. Muller F. Froland SS, Brandtzaeg P and Fagerhol MK. Oral candidiasis is associated with low levels of protid calprotectin in individuals with infection due to human immunodeficiency virus infection. Clinical Infectious Diseases 1993;16:301. 3. Myers CD. HIV and dietary supplements revisited. Brochure July 1993 (available at CATIE). 4. Tavares ]:), Salvador A, Fereira P and Arala-Chaves M. Immunological activities of a Candida albicans protein which plays an important role in the Survival of the microorganisms in the host. Infection and Immunity, 1993;61(5):1881-1888. 5. Hilton E, Isenberg HD, Alperskin P. et al. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Annals of Internal Medicine 1992;116(5):353-357. ACKNOWLEDGMENTS: 1. We thank CD Myers Ph.D. for helpful advice and comments. I. Living with drug-resistant fungus Background As the immune systems of patients with HIV/AIDS degrade they become at higher risk for various infections. Fungal infections caused by Candida in the mouth/throat and vagina can be common. Licensed in the late 1980s in the European Union the antifungal drug fluconazole (Diflucan(R)) has been used to treat a range of fungal infections in patients with AIDS. In general, the drug is low in toxicity (although it may be linked to the death of several patients) and effective against fungi infecting the mouth/throat and vagina. Once the infection has been contained patients will need maintenance therapy. Over time the fungus may begin to tolerate fluconazole. Patients with oral/throat fungal infections may have * "altered sense of taste" * "burning" or other pains in the mouth * pain when swallowing At this point doctors and their patients have a few options by switching to * ketoconazole 200 to 800 mg/day * higher doses of fluconazole 100 to 800 mg/day * oral amphotericm B--2 g/day * intravenous amphotericin B 50 mg/kg 3 times weekly * itraconazole capsules 200 to 400 mg/day * itraconazole liquid 200 to 400 mg/day Itraconazole capsules versus liquid Doctors in Britain have been experimenting with a liquid form of itraconazole (called itraconazole cyclodextrin 10 mg/ml). The researchers used 43 patients with HIV/AIDS who had fungal infections in their mouth/throat. At first these patients were using either ketoconazole, fluconazole or itraconazole capsules. As the fungi became tolerant of these drugs patients had more outbreaks of yeast infection. Doctors then prescribed the other drugs but the fungi eventually became resistant to them. Janssen, the manufacturer of itraconazole, produced the itraconazole liquid. Patients received 200 to 400 mg/day. Itraconazole Liquid The researchers found that 18 subjects recovered from the infection. The dose of itraconazole used did not seem to affect who recovered. Once the infection was stopped patients received either 200 or 400 mg/day as maintenance therapy. Patients using the 400 mg/day dose did not have another outbreak of yeast for about 3 months while those receiving the 200 mg/day doses relapsed about 2 months later. Itraconazole Liquid--Toxicity One patient had a rash but this cleared and did not appear when the patient resumed taking itraconazole. Eight patients had diarrhea but it is not clear if the liquid caused the diarrhea. One subject who later used 800 mg/day developed low blood levels of potassium. As yet, the best dose of liquid itraconazole with which to treat patients with drug-resistant fungi is not clear. Based on results from lab experiments, some researched are suggesting doses of 400 mg/day or more for such infections. References: 1. Sanguineii A, Cschael K, Campbell K. Fluconazole-resistant Candida albicans after long-term suppressive therapy. Archives of Internal Medicine 1993;153:1122. 2. Garber GE. Treatment of oral Candida mucositis infections. Drugs 1994;47(5):736740. 3. Baily GG, Perry FM, Denning DW and Mandal BK. Fluconazole resistant candidosis in an HIV cohorts AIDS 1994;8(6):787-792. 4. Menichetti F. Del Favero A, Martino P. et al. Preventing fungal infection in neutropenic patients with acute leukemia: fluconazole compared with oral amphotericin B. Annals of Internal Medicine 1994;120(11):913-918. 5 . Cartledge JD, Midgley J. Youle M and Gazzard BG. Itraconazole cyclodextrin solution effective treatment for HIV-related candidosis unresponsive to other azole therapy. Journal of Antimicrobial Chemotherapy 1994;1071-1073. 6. Barchiesi F. Colombo AL, McGough DA, et al. In vitro activity of itraconazole against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus. Antimicrobial Agents and Chemotherapy 1994;38(7):1530-1538. Toxicity A. AZT and fluconazole (Diflucan(R)) Background As the immune systems of people with HIV/AIDS weaken, patients become at increased risk for various infections. Instead of waiting for the infection to appear some patients are talking several antibiotics and antifungal drugs as prevention (prophylaxis). Most of these drugs are tested in subjects taking just one drug. Moreover, trials with these drugs often do not take into account the interaction among the various drugs. Patients talking these drugs may get unexpected side effects. Study Details Researchers in Ottawa enrolled 12 HIV-infected men with less than 500 CD4+ cells for this study. Subjects continued to use AZT 200 mg three times daily while in the study. Subjects received AZT and fluconazole and had blood samples taken at various times to check for blood levels of both drugs. Results Taking AZT and fluconazole caused subjects to have higher blood levels of AZT than when they did not take both drugs. This difference was statistically significant. The researchers are not sure precisely why this happened. What To Do? In another trial where some subjects received fluconazole (100 to 200 mg/day) to prevent a brain infection, subjects receiving fluconazole and AZT appeared more likely to have some bone marrow damage resulting in reduced levels of red and white blood cells. The Ottawa researchers suggest that patients receiving both AZT and fluconazole "should be monitored for [AZT toxicity]." References 1. Sahel J. Gallicano K, Pakuts A and Cameron DW. Effect of fluconazole on Zidovudine pharmacokinetics in patients infected with HIV. Journal of Infectious Diseases 1994;169(5):1103. B. Questions about gp160 vaccines Background In the mid-1980s, researchers had a relatively primitive model of HIV/AIDS. Some researchers thought that getting the body to produce antibodies against HIV might protect non-HIV-infected people from the virus and also delay the decline of the immune systems of people with HIV/AIDS. Information from the cutting edge of HIV/AIDS research suggests a more sophisticated model of HIV/AIDS. In this model, there is a complex interplay between the immune system and the virus. It is now clear that producing antibodies against HIV will not prevent the decline of the immune system. Indeed, some research suggests that producing antibodies against the virus may not be the best response by the immune system against HIV. Details on this appear in TreatmentUpdate 38 and 43. As well, the first generation of HIV vaccines using gp120 and gp160 has not protected uninfected people from HIV. The data reported about this research used information from subjects with HIV infection. Autoimmunity Shorty after AIDS appeared, researchers began to find clues that the immune system of patients with HIV/AIDS was attacking itself (a condition called autoimmunity). It appears that certain parts of HIV resemble key parts of the immune system. Antibodies cannot tell the difference between the virus and the immune system and simply attack whatever 'looks' like the virus. Some researchers think that autoimmunity plays an important role in weakening the immune system. Vaccines Now some researchers think that vaccines based on the HIV protein gp160 may cause the immune system to malice antibodies that attack itself. An Italian research team used blood samples from subjects who received certain vaccines: * rgp160 (VaxSyn2' by MicroGeneSys) * rgp120 HIVAC (Vacc-env by Bristol-Myers Squibb) Subjects who received the HIVAC did not make large amounts of antibodies against HIV. Once these subjects later received VaxSyn they then made detectable anti-HIV antibodies. Only subjects who received large doses of rgp160 made antibodies that could attack both the immune system and HIV. What Do These Results Mean This researcher found that "about 45% of [subjects] with full-blown AIDS, but none of the [symptom-free subjects] had antibodies [that attacked key parts of the immune system]." Readers should note that researchers are not certain that these will damage an immune system already battered by HIV. They do suggest that when scientists are designing vaccines that they should make ones that do not trigger autoimmunity. References: 1. Mosmann TR. Cytokine patterns during the progression to AIDS. Science 1994;256(5169):193-194. 2. Miedema F. Petit AJC, Terpestra FG, et al. Immunological abnormalities in human immunodeficiency virus-infected asymptomatic homosexual men: HIV affects the immune system before CD4+ T helper cell depletion occurs. Journal of Clinical Investigation 1988;82:1908-1914. 3. Katz-Miller S. Too early for vaccine trials say AIDS experts. New Scientist 25 June 1994, pages 6 to 7. 4. De Santis C, Robbioni P. Longhi R. et al. Cross-reactive response to human immunodeficiency virus type 1 (HIV-1) gp120 and HLA class I heavy chain induced by receipt of HIV-1-derived envelope vaccines. Journal of Infectious Diseases 1993;168:13961403. 5. Morow WJW, Isenberg DA, Sobol RE, et al. AIDS virus infection and autoimmunity: a perspective of tile clinicaL immunological and molecular origins of tile autoallergic pathologies associated with HIV disease. Clinical Immunology and Immunopathology 1991;58:163. Copyright (c) 1994 - CATIE "TreatmentUpdate". DISTRIBUTED BY GENA/aegis * 714.248.2836 * 8N1/Full Duplex * v.34.