Subject: Treatment Update #33 Date: May 1992 (564 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T U P D A T E && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TreatmentUpdate 33 By Sean Hosein -- May 1992 ISSN 11817186 --------------------------------------------- Community AIDS Treatment Information Exchange Reseau Communautaire D'info-Traitements Sida --------------------------------------------- Copyright (c) 1992 -- Permission 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 dementia B. HIV, mycoplasma and dementia C. AZT, ddI and muscle damage II IMMUNOMODULATORS A. Carnitine for muscle loss? B. CD8+ cells: therapy for KS? III INFECTION FIGHTERS A. Changing landscape of vaginal yeast infections B. Clinical trial of friendly bacteria in Canada ***** I ANTI-HIV AGENTS A. AZT and dementia Researchers in the USA have been conducting experiments on subjects with HIV infection who have developed problems related to memory and thinking. These researchers have been analyzing the CSF (cerebrospinal fluid -- in which the brain and spinal cord float) to look for laboratory markers which could be used to help diagnose patients with HIV-related dementia Samples of CSF from 78 subjects with HIV-related dementia were obtained. These were compared with CSF from 11 HIV-infected subjects without dementia. Of the 78 subjects with dementia, ten had CSF samples taken both before and after treatment with AZT. The researchers found that generally, the concentration of Beta2- microglobulin (B2m) in the CSF was significantly higher in subjects with dementia compared with HIV-infected subjects without dementia. B2m is a molecule produced by cells of the immune system such as macrophages and T-cells under the stimulation of interferon. Several studies have found that blood levels of B2m are elevated in people with HIV infection. In general, rising levels of B2m have been associated with worsening immune function. Moreover, several studies have found high levels of B2m in the CSF of patients with the AIDS Dementia Complex (ADC). Researchers in the USA have said that CSF levels of B2m could be used to separate patients with "anxiety and depression" (in which patients can have memory and thinking problems) from those with dementia. The researchers in this study also found that the more severe the dementia, the higher the level of B2m in the CSF. In 3 subjects with degeneration of the nerves affecting their ability to move, the level of B2m in the CSF was near normal. These subjects had been presumed to have HIV-related dementia because of their inability to move. Their memory and thinking functions remained normal. The precise cause of the nerve degeneration seen in these subjects is uncertain but some researchers have said that direct infection of the nerve cells by HIV is not the cause of nerve damage. High levels of B2m in the CSF were found not to be related "to the number of white blood cells in the CSF" or to the deterioration of the blood-brain barrier. Most of the 10 subjects who were treated with AZT had reduced levels of B2m in their CSF. This reduction in B2m levels corresponded with improvement in the symptoms of dementia. The exception was one subject taking 500 mg/day of AZT, which was the smallest dose given to any of the subjects. The best dose of AZT for treatment of dementia is uncertain but doctors find that generally, higher doses of the drug (1200 mg) tend to be more beneficial in such cases. According to the study researchers, there are still some unanswered questions concerning dementia. The researchers conducting the study were also looking for the cause of dementia in these subjects. This was difficult to find. According to the researchers the B2m found in the CSF was likely produced by HlV- infected cells of the immune system called macrophages that have been stimulated by interferon. Along with B2m, other possible laboratory markers which may be useful are neopterin and quinolinic acid. As well, precisely why administration of AZT causes a reduction of the symptoms of HIV-related dementia is uncertain. One answer may be that suppression of viral activity by the drug causes benefit. Again this is uncertain as few brain cells infected with HIV have been found by these or other study groups. Another possible explanation not raised by the researchers is that the immune suppressive effects of AZT (see TreatmentUpdate #26) on the production of interferons may provide benefit to treated subjects. An explanation of the potential of interferon-a to interact adversely with brain cells is in TreatmentUpdate #31. REFERENCES: 1. Brew BJ, Bhalla RB, Paul M et al. Cerebrospinal fluid B2- microglobulin in patients with AIDS dementia complex: an expanded series including response to Zidovudine treatment. AIDS 1992;6:461-465. 2. Tyor WR, Glass JD, Griffin W, et al. Cytokine expression in the brain during the Acquired Immunodeficiency Syndrome. Annals of Neurology 1992;31:349-360. ***** B. HIV, mycoplasma and dementia One possible consequence of HIV infection is a dysfunctional central nervous system. This can cause problems with some brain functions, including thinking, memory and sleeping patterns. Since direct infection of brain cells (neurons) by HIV is thought to be rare, there are likely several indirect ways HIV could cause brain dysfunction. Researchers in the USA (Walter Reed Army Institute) have been conducting experiments with neurons and HIV- infected cells. Their results may provide an insight into the possible cause(s) of brain dysfunction in some people with HIV. According to the American investigators, their experiments have shown that HIV and its proteins such as gp120 do not kill brain cells. Other investigators have found that in cases of AIDS-related dementia, brain samples contain macrophages and related cells. These researchers have speculated that dementia may be caused by HlV- infected macrophages in the brain. There is much experimental evidence to suggest that HIV-infected macrophages could be the cause of brain dysfunction. Macrophages are cells of the immune system which some researchers think are the main targets of HIV infection. As HIV-infected macrophages travel into the brain and other tissues they may spread HIV to previously uninfected parts of the body. HIV and several viral proteins such as gp120 might then disrupt communication between brain cells. There is also some evidence that HlV-infected macrophages produce excessive amounts of substances called cytokines (interferons, interleukins, tumour necrosis factor) which could be a possible cause of brain dysfunction. Macrophages also help repair damaged cells by producing a variety of substances. HIV-infected macrophages may produce chemicals toxic to brain cells resulting in their death. As well, the suppressed immune systems of patients with HIV infection may allow previously latent microorganisms to get out of control. Mycoplasma are microorganisms which have been shown, in laboratory experiments, to hasten the death of HIV-infected cells. The researchers at Walter Reed have created cultures of brain cells and HIV-infected macrophages similar to the conditions of those researchers who have reported instances of HIV proteins killing brain cells. The scientists at Walter Reed found that cultures treated with certain antibiotics -- which kill mycoplasma -- did not produce chemicals toxic to brain cells. It may be that contamination of laboratory equipment and cells by mycoplasma could account for the death of brain cells reported by other investigators. Certainly, the effect of mycoplasma as a laboratory contaminant or co-factor has been reported by other investigators in France. In France, scientists have isolated certain mycoplasma from people infected with HIV but not from those without HIV- infection. Other researchers in the USA have isolated mycoplasma in the brains of subjects with HIV- related dementia. There is experimental evidence which suggests that an interplay between mycoplasma, macrophages and HIV exists. For example, mycoplasma may "assist" HIV in killing cells. Another possible role is that mycoplasma infection may trigger inflammations as well as cause the immune system to attack itself. The precise role, if any, that mycoplasma play in HIV-infected people remains to be determined. REFERENCES: 1. Bernton EW, Bryant HU, Decosta MA, et al. No direct neuronotoxicity by HIV-1 virons or culture fluids form HIV-1 infected T-cells or monocytes. AIDS Research and Human Retroviruses 1992;8(4):495-503. 2. Root-Bernstein RS and Hobbs SH. Homologies between mycoplasma adesion peptide, CD4+ and class II MHC proteins: a possible mechanism for HIV-mycoplasma synergism in AIDS. Research in Immunology 1991;142:519-523. ***** C. AZT, ddI and muscle damage As more patients with HIV infection are treated with AZT (Azidothymidine, Retrovir, Zidovudine), ddl and other anti-HlV agents, reports of novel side effects, drug interactions or other complications become more frequent. In part this is because early research was focused on each drug's anti-HIV effect and the obvious side effects (life-threatening anemia, peripheral neuropathy, pancreatitis). Another reason is that some side effects only appear with prolonged use. One of the side effects which can appear in some patients given AZT is "muscle wasting". This is a gradual loss of muscles in various parts of the body. Researchers at UCLA and Cal Tech have been studying this side effect and have conducted experiments on rats in order to better understand how the drug causes muscle loss. Rats were fed AZT at a dose of approximately 10 times the dose usually prescribed to humans, for 35 days. Examination of the contents of muscle cells taken from various parts of the animals showed that AZT had clearly damaged some components of muscle cells. Indeed the researchers found that the damaged cell contents from AZT-treated rats were similar to muscle samples taken from "AZT-treated AIDS patients." Other researchers at Columbia University, New York, have performed experiments on HIV-infected subjects and found that prolonged use of the drug clearly damaged the contents of muscle cells. Subjects not given AZT shown no such damage. Moreover, comparison of muscle cells before administration of AZT with muscle cells taken after AZT was prescribed also found muscle cell damage. Another important observation from this study is that subjects who stopped taking the drug showed muscle tissue can recover once the drug is withdrawn. The New York researchers also cautioned that drugs similar to AZT such as ddC and ddI may caused depletion of muscle tissue. Although wasting of some muscles is considered by some to be just an esthetic problem, loss of muscle in the heart may pose more serious risks. Researchers at Johns Hopkins Hospital (Baltimore, Maryland) have been studying the effect HIV infection has on the heart. Given that AZT can cause muscle loss it is not surprising that some AZT-treated patients may experience cardiac problems. The doctors at Johns Hopkins studied 26 HIV-infected subjects who had "congestive heart failure" over a period of 2 years. Of these, 13 subjects were treated with AZT, and/or ddC and ddI. Six of the 13 subjects had "cardiac dysfunction clinically associated with [anti-retroviral therapy]." Four of the 6 subjects had worsening cardiac function when they were switched from AZT to ddl and or ddC. Most patients improved when anti-retroviral therapy was withdrawn. The doctors suggest that patients who develop "congestive heart failure while receiving anti-retroviral therapy be withdrawn from treatment for 1 month, followed by a non-invasive assessment of cardiac function. If antiretroviral therapy is resumed, cardiac status should be closely monitored." In addition to withdrawing AZT/ddC/ddI from patients, scientists in Italy have been conducting experiments with the compound carnitine. It may be that carnitine could be used by some patients to reduce muscle loss. Research on carnitine appears in the section on immunomodulators later on in this issue. REFERENCES: 1. Cegielski JP, Ramaiya K, Lallinger G, et al. Pericardial disease and Human Immunodeficiency Virus in Dar es Salaam, Tanzania. Lancet 1990;335:209-212. 2. Arnaudo E, Dalakas M, Shanske S, et al. Depletion of muscle mitochondrial DNA in AIDS patients with Zidovudine-induced myopathy. Lancet 1991;337:508-510. 3. Lewis W, Gonzalez B, Chomyn A and Papoian T. Zidovudine induced changes in rat skeletal muscle mitochondria. Journal of Clinical Investigation 1992;89(4): 1354-1360. 4. Herskowitz A, Willoughby SB, Baughman KL, et al. Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: A report of six cases. Annals of Internal Medicine 1992;116(4):311-313. 5. De Jong MD and Borleffs JCC. Didanosine and heart failure. Lancet 1992;339;806-807. ***** [Some text appears to be missing, the beginning of Section II, Part A.] B. CD8+ cells: therapy for KS? The infusions of CD8+ cells did not cause any toxic effects. Although some subjects experienced muscle aches and "low-grade fevers" these were thought to be side effects of IL-2. Although the aim of the study was to determine the safety of the procedure, some data on efficacy were collected. One subject at the start of the study had 80 CD4 ' cells and "aggressive KS" which had spread to lymph nodes causing fluid retention in the legs. In the past, this subject had not responded to interferon-a~ therapy even though his CD4+ was approximately 400 cells at the time. Over the 6 months of the study, the ability of his cells to destroy foreign cells increased from 7% to 30%. This subject had 70% of his lesions regress. His quality of life dramatically improved. Six weeks after his last infusion the lesions reappeared and he died within 9 months. Another subject experienced a 50% reduction in the size of his oral KS lesion. Lesions on his face also regressed although those "on the rest of his body were not significantly improved. Two of the 4 other subjects had a clearing of their oral hairy leukoplakia, something which "does not usually resolve spontaneously", according to the study doctors. None of these 4 subjects had significant changes in their CD4+ cell counts during the 6-month period of the study. In simulated tests, the ability of natural killer cells (NK cells) to destroy target cells improved. The Miami researchers found that CD8+ extraction and reinfusion causes "minimal" adverse reactions. They suggest that trials using more subjects be performed as there are still many questions left unanswered. For instance, does this therapy work best in certain populations such as those with high CD4+ counts and minimal symptoms? How often do infusions need to be given? The researchers are not certain about the best "dose" of CD8+ cells to infuse into subjects. Neither are they sure if drugs other than AZT could be used in these subjects. REFERENCES: 1. Kilmas NG, Fletcher MA, Walling J et al. Clinical impact of adoptive therapy with purified CD8+ cells in HIV infection. Seminars in Oncology 1992;April:40-44. ***** III INFECTION FIGHTERS A. Changing landscape of vaginal yeast infections Over the past 30 years, women in North America have increasingly experienced yeast infections in the vagina (vaginal candidiasis: VC) caused by various species of the fungus Candida. In the USA at least 13 million cases of VC are being reported on an annual basis. Most of these infections have been caused by one species; Candida albicans. There may be several reasons for the increased incidence of VC. Some researchers think that the widespread use of antibiotics plays a role. Antibiotics kill microorganisms and thus alter the balance among the various bacteria and other organisms in the vagina. As the bacteria die, growth of yeast once kept in check by bacteria can now expand and colonize more of the vagina. Another possible cause of the increased incidence of fungal infections is the use of oral contraceptives, although this is controversial. Whatever the cause, the increase in yeast infections is troubling. Not only do women now have to contend with more infections but it seems that more and more yeasts are developing resistance to antifungal agents such as nystatin, clotrimazole and miconazole. There are also reports that yeast infections, despite adequate treatment, appear to be recurring more frequently. Exactly why some women develop chronic yeast infections is also controversial and uncertain. For instance, some studies have found that yeast from the women's sex partners is likely the source of infection. Yet, despite several controlled trials where the women's male sex partners have been treated, women still develop recurrent yeast infections. Thus it is thought that the source of these infections may come from yeast resident in the intestine. Several studies, however, have not found this to be the case. Inadequate treatment is thought to be a possible cause of relapse. According to one study it is estimated that as many as 20% of women who become yeast-free as a result of therapy, become re-infected within 1 to 3 months. Other factors which may play a role include altered immunofunctions and diets high in sugar. It is possible that immunologic changes as a result of Candida infection can occur. Exposure to Candida can result in some suppression of T-cell function and dysfunction in other parts of the immune system. It has also been found that other species of Candida are becoming increasingly implicated as the cause of infection. These other yeasts were more likely to be found in women who have used the diaphragm together with contraceptive jellies. Apparently spermicidal creams and jellies alter the normal balance of microorganisms in the vagina. Spermicides also allow fungi to stick to the mucous membranes of the vagina. There is some evidence that current drug regimens for vaginal yeast infections are not adequate for proper treatment. The use of anti-fungal agents for very short periods of time has allowed fungi not affected by these drugs to survive. Shorter courses of anti-fungals have become more widely used in an effort to get patients to comply with the treatment regimen. Originally, treatment usually lasted for 2 weeks. Recently, this has been shortened to 3 or even 1 day regimens. Although the shorter regimens are popular with patients, the 2 week regimens are usually more effective than the 3 or 1 day regimens and relapse is less likely. Researchers in the USA have been studying the problem of yeast infections and have developed some strategies. According to doctors who have studied the reasons for treatment failures, it is important to get a laboratory analysis of the species of Candida which is causing infection. They caution that it is difficult to rely on physical signs alone because different species of Candida can cause similar symptoms. After laboratory assessment, the American doctors recommend that longer treatment regimens (such as those lasting for 2 weeks) be prescribed. For doctors who are unable to get laboratory analysis, the use of antifungals with a wide spectrum of activity should be useful. These drugs should kill several species of Candida and relapse is less likely. Terconazole is one example of a broad-spectrum antifungal. In clinical trials, the drug is effective and has few toxic effects. An advantage in using terconazole is that the drug remains at high concentrations in the vagina days after it was last applied, resulting in sustained fungal suppression. The drug fluconazole (Diflucan) is also effective in the treatment of vaginal yeast infections. The American doctors suggest that use of "over-the-counter" anti-fungals for short periods of time may prove, in the long-term, not to be the best form of therapy for patients for many of the reasons already listed. Diagnosis of which yeast is the cause of infection seems to be the first step in establishing a treatment strategy for vaginal yeast infections. For women with HIV infection, recurrent yeast infections can occur despite lengthy periods of treatment. This may be due the dysfunctional behaviour of the immune system's cells in the vagina. It is thought that perhaps agents which could improve immunofunction may be useful. Changing diets to reduce sugar is one helpful step. At a recent forum on treatments for HIV/AIDS, it was noted that some women find douches of yogurt with "active" friendly bacteria helpful in the prevention of vaginal yeast infections. Others have reported douches of the herbs goldenseal and echinacea beneficial. In a future issue of TreatmentUpdate, research on extracts of echinacea will be presented. Another strategy which might be useful is to use capsules of friendly bacteria in the vagina. The next article will describe some research in Toronto with these organisms. REFERENCES: 1. Horowitz BJ, Giaquinta D and I to S. Evolving pathogens in vulvovaginal candidiasis: implications for patient care. Journal of Clinical Pharmacology 1992;32:248-255. 2. Bihari B. Managing HIV infection: A free forum for people living with HIV and for health care providers. Lecture 30 May, 1992. Toronto, Ontario. ***** B. Clinical trial of friendly bacteria in Canada Some women have problems with recurrent urinary tract infection (UTI). The standard treatment is usually Bactrim/ Septra or nitrofurantoin. Prevention or prophylaxis usually consists of low-dose Bactrim/Septra. A side effect of this antibiotic therapy is that useful microorganisms which normally live in the urinary tract and intestine are often killed. Bacteria such as lactobacilli feed on milk sugar in the intestine and produce vitamins which can be absorbed by their human hosts. These bacteria are thought to keep the growth of unwanted and harmful microorganisms in check. Exactly how the bacteria do this is not certain but bacteria such as Lactobacilli may release chemicals such as lactic acid which inhibits the growth of yeasts. Antibiotic therapy thus upsets the interplay among the various bacteria and fungi. Since yeasts are not usually affected by antibiotics, they can then move in on the areas formerly colonized by bacteria. Overuse of antibiotics is thought to be one of the factors linked to recurrent vaginal yeast infections. For women with HIV infection, recurrent vaginal yeast infections can be a serious problem. Now, perhaps an alternative method of preventing such infections is possible. Researchers in Toronto enrolled 41 women who had not yet entered menopause. Each subject was randomly given 1 of 2 antibiotics to be used over a 3-day period: norfloxacin (200 mg/day); or Bactrim/Septra (160/80 mg/day). On the 3rd day of the study, subjects were randomly assigned to receive capsules of friendly bacteria (Lactobacilli) or sterile powdered milk (a placebo) capsules. Subjects were instructed to place a capsule in their vaginas twice weekly for 2 weeks. After that time then the capsules were to be inserted "at the end of the next 2 months." Urine and swab cultures were done on a regular basis to identify vaginal microorganisms. The researchers found that both antibiotics were effective in treating "acute and uncomplicated" UTIs. Among subjects who experienced relapses the causative organism was never the friendly bacteria. Vaginal use of lactobacilli was found to be safe. Subjects given placebo experienced a recurrence rate of 47% while those given friendly bacteria had a rate of only 21%. The researchers did say that the number of subjects used was not based on requirements to calculate effectiveness. The number of women enrolled were only to test for the safety of the bacteria. Doctors who have given antibiotic therapy to women with UTI may find the use of friendly bacteria by their patients an alternative method of preventing relapse. REFERENCES: 1. Reid G, Brue AW and Taylor M. Influence of 3-day antimicrobial therapy and lactobacillus vaginal suppositories on recurrence of urinary tract infections. Clinical Therapeutics 1992;14(1):1116. ***** TREATMENTUPDATE 33 Editor: Sean Hosein Production Manager: Sean Hosein Copy Editing: Alex Berry Desktop Publishing: Alex Berry Proofreading: John Hammond Distribution: Bill Naumovich, Jack Reynolds, Harry Collie, John Guenther Subscriptions: Jack Reynolds ***** DISCLAIMER The Community AIDS Treatment Information Exchange (CATIE) publishes TreatmentUpdate/TraitementSida as an information 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. Individuals 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 TreatmentUpdate/ 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 in this publication must do so at their own risk. SUBSCRIPTIONS CATIE, Ste 324, 517 College Street Toronto, Ontario, Canada M6G 4A2 &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display