TreatmentUpdate43 Community AIDS Treatment Information Exchange By Sean Hosein - Volume 4, No. 3, 1993 ISSN 11817186 CONTENTS I HIV/AIDS THEORY A. HIV--new discoveries and important findings B. HIV--infection continues even when there are no symptoms C. Can the immune system survive attacks by HIV? D. The chemicals of change E. Repairing the immune system II IMMUNOMODULATORS A. DNCB and the immune system B. DNCB--previous use and toxicity C. Results from a pilot study of DNCB D. How DNCB works III TOXICITY A. Drug toxicity B. AZT and related drugs C. Types of reactions D. Bactrim/Septra and sulpha for PCP E. Drugs for PCP--pentamidine F. Other drugs for PCP G. Anti-fungal drugs H. Drugs for Toxo I. Drugs for MAC and TB J. Methadone and other drugs ********** I. HIV/AIDS THEORY A. HIV new discoveries, important findings First isolated 10 years ago in Paris, HIV is now the focus of intense research. Recently several advances have been made in scientists' under- standing of the way HIV damages the immune system. These findings can be divided into 2 basic areas: * the importance of lymph nodes * the interaction between HIV and the immune system The usefulness of this research is that scientists can at last begin designing effective therapies for people with HIV infection/AIDS. In the sections to follow we will report some of their research and possible therapies for HIV/AIDS. It is important that people try to understand this new research, if only to steer themselves clear of therapies which may be toxic and have no survival benefit. B. HIV--infection continues even when there are no symptoms of illness o Background Working independently of each other, two research teams of virologists in the USA have made some interesting discoveries about the lymph nodes of people with HIV infection. As well, scientists, who study the immune system have made important advances in understanding how HIV infection can damage the immune system.We now report their findings in point form: * Throughout the course of HIV infection, most of the virus is located in lymph nodes/organs/tissue (including bone marrow, spleen, thymus gland, tonsils, appendix, intestines, lungs and skin). * Most CD4+ cells and macrophages in lymph nodes/ organs are infected with HIV. As CD4+ cells are concentrated in those areas it is no surprise that a deficiency of these cells occurs. This finding does not mean that direct infection by HIV of CD4+ cells is the only way those cells are destroyed. There is evidence that CD4+ cells are attacked by the immune system. As well, CD4+ cells are just one part of the immune system and there may be other parts that are involved in the immunodeficiency in AIDS. * The gradual destruction of lymph nodes/organs probably reduces the body's ability to contain HIV infection. There are between 500 and 1000 lymph nodes in the body. Although researchers have documented the presence of damaged lymph nodes, they do not know if all the lymph nodes are severely damaged in people with AIDS. * HIV replication continues in the lymph nodes/organs even when patients are symptom-free. Thus, there really is no such thing as a "latency period" in people with HIV infection. * Cells of the immune system taken from the blood do not provide a correct "picture" of HIV replication in the body. * As the production and spread of HIV is increased when the entire immune system becomes "activated" it is probably important that other infections be treated and/or suppressed. Thus preventative, intermittent doses of antibiotics, which can restrict the spread of various infections, may help delay the decline of the immune system. One problem with this is that some drugs are toxic to the immune system in general and T-cells in particular. Patients and their doctors will have to carefully weigh the risks and benefits of these drugs. * Finally, and perhaps most important of all, under constant attack by HIV, the immune system changes its response. Understanding how and why this shift happens appears to be critical if an "effective" therapy for HIV infection is to be made. But the immune system does not always "lose" the fight against the virus. In the next section we report on work which suggests that there are people who can encounter and survive HIV infection. REFERENCES: 1. Panteleo G, Graziosi C, Demarest JF, Butini L, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993;362:355-358. 2. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993;362:359-362. 3. Shearer GM and Clenci M. T helper cell immune dysfunction in asymptomatic, HIV-1-seropositive individuals:the role of Th1->Th2 cross-regulation. Chemical Immunology 1992;54:2143. 4. Gougeon M-L, Colizzi V, Dalgleish A and Montagnier L. New concepts in AIDS pathogenesis. AIDS Research and Human Retroviruses 1993;9(3):287-289. 5 . Castenholz A. Architecture of the lymph node with regard to its function. Current Topics in Pathology 1990;84(part 1):1-32. C. Can the immune system survive attacks by HIV? o BACKGROUND For much of the past decade of the AIDS epidemic most researchers assumed that everyone exposed to HIV would eventually develop AIDS. In part this is because HIV infection results in a huge loss of "CD4+ T-helper cells" (also called T4+ cells) which makes patients prone to certain infections and cancers. Even the prospect of protecting uninfected people with a vaccine seemed dismal as HIV mutates rapidly. o IMMUNOSUPPRESSION OR IMMUNE DYSFUNCTION? There are some aspects of HIV infection that are confusing. For instance, the number of CD4+ cells declines over time. On the other hand the activity of antibody-producing B-cells increases. Even when the CD4+ count is over 500 cells, the performance of these T-helper cells is below normal. Recently, some researchers have been reporting that there are people whose immune systems have apparently encountered HIV and yet remained intact. o SUCCESSFUL DEFENSE AGAINST HIV Scientists at the NCI's Experimental Immunology Branch (National Cancer Institute, Bethesda, Maryland) have been studying large numbers of people who have been exposed to HIV on several occasions and yet have remained healthy and HIV antibody-negative (that is, they did not produce anti-HIV antibodies). The NCI researchers have been conducting extensive and sophisticated experiments on the cells of the immune system from these people to find out how and why they managed to remain healthy. For comparison, similar work was done on blood samples from people with HIV infection at different stages of illness. What these researchers have found is a way to assess the decline in the "performance" of T-helper cells. o WHAT THESE TESTS MEAN The researchers tested over 600 HIV-infected but symptom-free subjects to see how their T-helper cells would respond. As well, the researchers monitored the subjects to see how their health declined. Compared to subjects who responded to all the tests, the researchers found that subjects whose T- helper cells did not react to one or more of the tests were more likely to have: * a steep decline in their CD4 ' cell counts * more life-threatening infections (in HIV-infected children) * a higher chance of developing life-threatening infections and/or cancers * higher levels of Beta2-microglobulin in their CSF (cerebrospinal fluid in which the brain and spinal cord float) They noticed that when improvements in T-helper cell activity happened patients remained relatively free of infections. Increases in the CD4+ cell counts did not have the same effect. Thus "loss or recovery of [T-helper] cell function can occur...independently of changes in the CD4+ count. o WHY DOES THE PERFORMANCE OF T-HELPER CELL Activity DECLINE? The precise cause of this loss of T-helper cell activity is not yet clear but there are a number of possibilities, including: * toxicity from anti-virals, antibiotics and other drugs * loss of "memory" T-cells * a defect in one of the immune system's key defenses (described by researchers as APCs; antigen presenting cells) * the production of antibodies which impair the functioning of APCs * the presence of immunosuppressive chemicals; either parts of HIV or * products from HIV-infected cells * chemicals produced by the immune system which derail attempts to contain HIV infection o ANTIBODIES In order to explain several ideas about the immune system we will describe them in a highly simplified way. There are two basic parts in the immune system. The part that is involved with antibody production is called humoral immunity. In cases of the common cold, nu and certain bacterial infections, producing antibodies can be useful as they attack individual microorganisms that are lurking outside cells of the body. However, most of the serious infections people with AIDS get involve microorganisms that get inside cells. In such cases antibodies are of little use. o CMI The other arm of the immune system is called CMI (cell-mediated immunity). The cells that perform this function include NK (natural killer) cells, activated macrophages and CD8+ cells. These cells can destroy HIV- infected cells and do not produce antibodies. In HIV/AIDS, for reasons mentioned before, CMI is dysfunctional and this allows certain infections/tumors to get out of control. o TWO TYPES OF CD4+ CELLS: The following passage is reprinted with the kind permission of the author, B. Goldberg. "There are two types of CD4+ cells. The first type or Th 1 [starts the process] of delayed hypersensitivity which [activates] CMI. The CD8+ cells that are activated by Th 1 are known as Tl. The second type of CD4+ cells [triggers] the antibody response and is known as Th2. The CD8+ cells in this Th2 response suppress CMI and are known as T2. What is critical is that the opportunistic infections and HIV in AIDS are in the cells and can only be controlled by cellular immunity (Th1/T1)." By themselves counting CD4+ cells is not a sophisticated way to go about finding out what condition the immune system is in. This is because some CD4+ cells "can be Th1 (good) or Th2 (bad). The absolute CD8+ cell count is probably more useful in predicting the [appearance of, and the body's response] to opportunistic infections." o THE IMMUNE SYSTEM SHIFTS GEARS Researchers at the NCI have found that people with HIV infection undergo a shift in their immune response. That is, from a CMI (Th1) response to a more humoral (Th2) response. This happens gradually so that by the time AIDS develops the shift has largely happened. In the next section we explain how some researchers think this shift happens. D. The chemicals of change IL-2 (interleukin-2) is an important T-cell growth factor. According to the NCI scientists people with HIV infection produce less and less of this chemical over time. At the same time more and more of IL-4 is produced. By the time AIDS occurs the level of IL-4 has started to fall, while levels of another chemical IL-10 increase. Thus what is happening is that the Th2 response becomes activated and this reduces the Th1 response. This conversion of the Th1 response is done by chemical messengers of the immune system called cytokines (interferons, interleukins). It is likely that IL-4, IL-6, IL-10, and IL-13 play a role in suppressing Th1 responses. o WHY ARE SOME PEOPLE ABLE TO RESIST HIV? The results of the experiments by the NCI researchers suggest that those subjects who were repeatedly exposed to HIV and who remained healthy and HIV-antibody negative had an immune response that was described as Th1. This CMI (cell-mediated-immunity) was able to keep the infection under control. Even when these subjects were re-exposed to HIV their Th1 response kept them healthy. E. Repairing the immune system Analysis of the work done by NCI scientists suggests that maintaining CMI (the Th1 response) can "prevent HIV infection and/or progression to AIDS." This has implications for the care and treatment of people with HIV infection: * Infections (other than HIV) which can cause the immune response to switch from one based on CMI to that based on antibody responses could act as cofactors, speeding up the decline of the immune system. Examples of these types of diseases might include tuberculosis (TB) and syphilis. Thus diagnosis, treatment and prevention of other infections becomes increasingly important. * Instead of giving HIV-infected subjects large doses of the viral proteins gp160 and gp120 in vaccination experiments, perhaps very small doses should be used instead. Low doses might be enough to stimulate T-cell functions but not strong enough to trigger the production of antibodies by B-cells. * Screening people with HIV infection into those with a good CMI response from others with a good humoral response could be a first step in a new direction for therapy. Those subjects with a good humoral response could be given antibodies that attacked IL-4, IL-10 and other chemicals of the immune system. This may return their immune response to a more effective phase. Researchers at military biomedical centres in the USA have performed experiments on T-cells taken from people with a good humoral response. They exposed those T-cells to antibodies that attacked IL-4 which then reversed the decline in CD4+ cell functioning. * Other ways to boost cell-mediated immunity could include giving people infusions of low dose interferon-gamma and IL-2. * Dr. Jonas Salk and researchers at the NCI have proposed that very low doses of the live TB vaccine (BCG) could also help but this has to be tested for safety in experiments before being given to larger numbers of people with HIV infection. * Based on this research there may be a limited role for the immune boosters acemannan (Carrisyn(R)), DNCB and the hormone DHEA in maintaining T-cell functions. We should point out that researchers do not know the best dose and schedule for using DHEA in people with HIV infection. None of these three drugs is a cure for AIDS. As research in this field is only just beginning to occur it will be some time before researchers learn which combination of these or other agents will be most useful. REFERENCES: 1. Clerici M, Shearer GM. A TH1->TH2 switch is a critical step in the etiology of HIV infection. Immunology Today 1993;14(3):107-111. 2. Goldberg B . Cellular and antibody immune responses in AIDS (personal communication*). *Data on file at CATIE. 3. Clerici M, Hakim FT, Venzon DJ, et al. Changes in interleukin- 2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. Journal of Clinical Investigation 1993;91:759-765. 4. Romagnani S. Human Th1 and Th2 subsets:regulation of differentiation and role in protection and immunopathology. International Archives of Allergy and Immunology 1992;98:279-285. 5. Fitzgerald TJ. The Th1/Th2-like switch in syphilitic infection:is it detrimental? Infection and Immunity 1992;60(9):3475-3479. 6. Meyaard L, Schuitemaker H and Miedema F. T-cell dysfunction in HIV infection: anergy due to defective antigen-presenting cell function? Immunology Today 1993:161 7. Knight SC, Macatonia SE and Patterson S. Infection of dendritic cells with HIV-1: virus load regulates stimulation and suppression of T-cell activity. Research in Virology 1993;144:7580. 8. Salk J, Bretscher PA, Salk PL, et al. A strategy for prophylactic vaccination against HIV. Science 1993;260:1270-1272. 9. Manetti R, Parronchi P, Giudizi M, et al. Natural killer cell stimulatory factor (Interleukin-12 [IL-12]) induces T helper type 1(Th1) specific responses and inhibits the development of IL-4 producing Th cells. Journal of Experimental Medicine 1993;177:1199-1204. II. IMMUNOMODULATORS A. DNCB and the immune system DNCB is a chemical used to develop color film. It has also been used in air conditioning and refrigeration equipment. Medically, DNCB has been used in crude tests of immunofunctions. For this purpose DNCB is usually dissolved in alcohol or acetone and then put on the skin. There the compound causes a minor allergic reaction, restricted to the small area where DNCB was applied. DNCB penetrates the skin and comes into contact with cells of the immune system known as Langerhans cells and macrophages. These cells "notice and capture" the DNCB and present the compound to CD4+ cells as an intruder. The immune system is then activated. When DNCB is placed on the skin two to four weeks later the reaction--swelling and redness is usually faster compared to the first time the drug was applied to the skin. B. DNCB previous use and toxicity potential o WART VIRUS INFECTIONS In the past DNCB has been used to treat wart virus infection by putting a solution of the drug directly on to wart virus lesions. Applying the drug to the shoulder where there were no lesions has also caused recovery from wart virus infections in about 78% of patients. This suggests that applying DNCB to one site may activate the entire immune system. o HAIR LOSS In one hair loss condition known as alopecia areata (an autoimmune disorder caused by a viral infection), DNCB treatment has caused regrowth of hair. The standard treatment for this has been immunosuppressive drugs. Some researchers suggest that DNCB may correct the underlying immune dysfunction in this disorder. o ANIMAL EXPERIMENTS DNCB has also been used to treat animals with cancer. When applied directly to skin cancer lesions, the lesions have been observed to disappear. Previously undetected and precancerous lesions have been rendered visible by use of DNCB on the skin of these animals. o TOXICITY--CANCER AND DRUG ALLERGIES As DNCB is derived from the chemical benzene there are concerns that it may promote the growth of cancers. However, there has been no detectable toxicity in lab animals fed DNCB. Doctors monitoring people with HIV infection who have used DNCB for at least 3 years have not reported the detection of tumors. Since DNCB "resembles" the drug chloramphenicol and related compounds, some researchers thought that sensitivity to DNCB might make treated patients allergic to those drugs. Experiments on humans with DNCB have found that this does not happen. o TOXICITY- FOOD FOR THE VIRUS THEORY Some researchers have said that use of immune boosters may stimulate the immune system, increase production of HIV and place more cells at risk for HIV infection. Laboratory experiments with cells and HIV have found that increasing the number of CD4+ cells has not caused more of these cells to die. Moreover, results from long-term experiments on HIV-infected humans have found that use of DNCB may do the following: * reduce viral replication and * maintain the number of CD4+ cells In the next section we will report on findings from a recent pilot study of the drug in people with HIV infection. REFERENCES: 1. Stricker RB and Elswood BF. Dendritic cells and dinitrochlorobenzene (DNCB): a new treatment approach to AIDS. Immunology Letters 1991;29:1191-196. 2. Stricker RB and Elswood BF. Topical dinitrochlorobenzene in HIV disease. Journal of the American Academy of Dermatology 1993;28(5):796-797. C. Results from a pilot study of DNCB in HIV infection o SUBJECTS Researchers at the University of California at San Francisco and at the California Pacific Medical Centre (also in San Francisco) have recently had the results of their experiments on humans published. Twenty subjects infected with HIV were recruited for this study. At the start, the average CD4+ count was 347 cells (counts ranged from 100 to 600 CD4t cells). Sixteen subjects had no symptoms and the remaining 4 subjects had persistently swollen lymph nodes. Nine subjects were taking AZT before the study began and they continued to use that drug at the same dose during the trial. Subjects who had life-threatening infections and/or cancers were not allowed to enter the study. Overall, subjects were observed for an average of 12 months, others for as long as 20 months. Two subjects left the study; one because of "cosmetic effects" and the other because he was encouraged by his family doctor to leave. These two subjects continued to be monitored and used as "controls". o DNCB PROTOCOL--PART 1 DNCB was dissolved into a solution of acetone. Subjects were given solutions of DNCB in various concentrations (10%, 2%, 0.2% and 0.02%). A small amount of 10% DNCB solution was put on a 25-millimetre patch of skin "usually on the forearm." Over the next 3 days swelling and redness at this site should have occurred. If this did not happen subjects "repeated this dose at weekly intervals until sensitization [redness, swelling, itching] occurred." o DNCB PROTOCOL--PART 2 Once this sensitization happened subjects were supposed to put some of the 2% DNCB solution on a another patch of skin (25 mm) on the "forearm or upper arm" once per week. As subjects continued in the trial the site where DNCB was first placed would swell turning red or itching (this reaction is described as a "reflare"). According to the researchers involved with the study this reflare confirmed that the immune system had been "sensitized" to DNCB. Once this happened subjects were told to decrease the weekly dose of DNCB to the weakest concentration that caused this reaction. o RESULTS--CD4+ CELLS Before the use of DNCB the average CD4+ count was 347 cells. After use of DNCB the count was 343 cells. This change was not statistically significant and the CD4+ counts were considered stable. There were no statistically significant differences in CD4+ cells between those on AZT and others not using AZT in this study. o RESULTS--CD8+ CELLS Before using DNCB the average CD8+ cell count was 904 cells. After becoming sensitized to DNCB the CD8+ count increased to 1068 cells. This increase was statistically significant. This increase happened whether or not subjects used AZT. Over the first 6 months of the study the increase in CD8+ cells continued. Please see the section D for how DNCB works. o RESULTS--NK CELLS NK (natural killer) cells are important in cancer control and can perform anti-viral activities. Increases in NK cells from an average of 95 cells to 119 cells were noted. This increase was statistically significant and happened in subjects whether or not they used AZT. o RESULTS--SYMPTOMS No subject developed a life-threatening infection and/or cancer during the study. o RESULTS--HIV REPLICATION Using quantitative PCR (polymerase chain reaction), tests were done to measure the amount of the HIV enzyme RT (reverse transcriptase) in the lymphocytes of 11 subjects. In 9 subjects using DNCB there was a significant decline in the amount of this HIV enzyme while in the 2 control subjects the amount of HIV in their lymphocytes increased. o RESULTS--SIDE EFFECTS DNCB exposure was described as "safe" by the study doctors; no subjects experienced any life-threatening reactions. In 2 subjects "burning, itching and [inflammation and redness]" occurred during the study. Over a period of 2 days this reaction went away. According to the study doctors, "most subjects experienced some initial discomfort at the application site." o TRIAL SUMMARY DNCB is known to improve some immunofunctions. Applying a solution of this drug to the skin appears to have an effect on the whole immune system. Cells of the immune system in the skin which are "exposed to DNCB" are thought to stimulate CD8+ and NK cells. Both types of cells can have anti-viral activity. CD8+ cells can produce an anti-viral substance (researchers are not certain just what this substance is) which may explain the decrease in the amount of HIV in the lymphocytes of DNCB-treated subjects. Use of DNCB may stabilize the decline of immunofunctions in some people with HIV infection. Interestingly, DNCB stimulation of the immune system did not cause the CD4+ cell count to decrease significantly. PCR tests suggested that HIV production either remained constant or fell to a low level as a result of DNCB use. References are at the end of section D. D. How DNCB works DNCB may help shift the immune response from one based largely on antibody production to one where the body's CD4+ and CD8+ T-cells, macrophages and NK cells can mount sustained attacks on HIV-infected cells. CD8+ cells are " a major defense against viral infections and intracellular parasites." Keeping this arm of the immune system active appears to be increasingly important in containing HIV infection. The San Francisco researchers suggest that larger trials be done to confirm their findings. Doctors in that city and Toronto are thinking about conducting a large, observational study of DNCB in people with HIV infection. o DNCB--NOTES FROM THE 1980s One prominent American AIDS-researcher told TreatmentUpdate that he and other doctors monitored their patients who were using DNCB in the mid-1980s. They noticed that while the CD4+ cell counts remained stable the CD8+cell counts went up. This caused the CD4/ CD8 ratio to fall. At that time some doctors felt that CD8+ cells "suppressed" the immune response and were "bad" cells. He and other physicians then discouraged their patients from further use of the drug. However, recent research in North America and the EC suggests that CD8+ cells are important, and maintaining or increasing the CD8+cell count may protect against life-threatening infections and/or cancers. He plans to analyse his patients' records to see what effect DNCB might have had on the appearance of life-threatening infections and/or cancers and survival. Further information on CD8+ cells and HIV infection will appear in a future issue of TreatmentUpdate. o DNCB SUPPLY The DNCB used in their experiments was supplied by HAF (Healing Alternatives Foundation) in San Francisco. DNCB is not patented by any pharmaceutical company and is thus very cheap; a DNCB kit from HAF with a 1 year supply is about $30 US and includes instructions for use. Because it is not patented there are no large profits to be made from the sale of DNCB. Thus there is no financial incentive to pay for large clinical trials of this apparently low-toxicity drug. REFERENCES: 1. Stricker RB, Zhu YS, Elswood BF, et al. Pilot study of topical dinitrochlorobenzene (DNCB) in human immunodeficiency virus infection. Immunology Letters 1993;36:1-6. 2. Cameron PU, Forsum U, Teppler H, et al. During HIV-1 infection most blood dendritic cells are not productively infected and can induce allogenic CD4+ T-cell clonal expansion. Clinical and Experimental Immunology 1992;88:226-236. 3. Meltzer MS and Nacy CA. Delayed-type hypersensitivity and the induction of activated, cytotoxic macrophages, in Fundamental Immunology, pages 765-767. Second edition, William E. Paul editor. Raven Press, New York, 1989. 4. Erad F, Wild M-T, Gareia-Sanz JA and Le Gros G. Switch of CD8+ T cells to noncytolytic CD8 CD4 cells that make Th2 cytokines and help B cells. Science 1993;260: 1802-1805. 5. Fiala M, Kermani V and Gornbein J. Role of CD8+ in late opportunistic infections of patients with AIDS. Research in Immunology 1992;143:903-907. 6. Bird AG and Watret KC. CD8 T lymphocyte subset markers and HIV infection. Editorial Review. Clinical and Experimental Immunology 1992:90:355-356. 7. Mody CH, Chen G-H, Jackson C, et al. Depletion of murine CD8+ T cells in vivo decreases pulmonary clearance of a moderately virulent strain of Cryptococcus neoformans. Journal of Laboratory and Clinical Medicine 1993;121:765-773. Acknowledgments: 1. We are grateful to B. Goldberg for advice, comments, support and gaining access to research, treatment activists and scientists, all of which was very helpful in understanding the complex immunology involved in writing these articles. III. TOXICITY A. Drug toxicity People with HIV infection seem more likely to experience allergic reactions to and toxic effects of certain drugs. Researchers are not sure why this happens. In this issue of TreatmentUpdate we will focus on common drug interactions and symptoms of drug toxicity which may be seen when patients use drugs for PCP/toxo, MAC/TB, anti-fungal drugs, and methadone. In the next issue we will have the same information on anti-cancer agents and drugs for herpes viruses. We do not have room for the vast number of side effects that may be caused by each drug. This is just a partial list of the more common adverse reactions and drug interactions that may be experienced by some people with HIV infection. Not every person will experience every side effect. Moreover, the same side effect may be mild in one patient and serious in another. Careful monitoring may allow doctors to rescue patients from the toxic effects of drugs. Articles on the toxicity of certain drugs on the immune system will also appear in future issues of TreatmentUpdate. B. AZT and related drugs The toxicities of AZT and ddI have been described in past issues of TreatmentUpdate. The toxic effects of AZT on the immune system are reported in TreatmentUpdate 24, 26 and 41. Side effects of ddI appear in TreatmentUpdate 25 and 27. o DDC Painful damage to the nerves in the feet and hands (peripheral neuropathy) can happen in as many as 33% of patients. Other side effects include ulcers, rash, headache and nausea. C. The types of reactions In general, the adverse reactions and drug interactions which appear in this issue of TreatmentUpdate have not been published in past issues. In some cases we will report on ways to deal with these side effects. Most side effects can be broken down into 5 groups: * Skin reactions: rashes, redness, itching, sensitivity to sunlight * Shock ("anaphylactic-like reaction") * Fever * Liver damage: usually detected by increasing blood levels of liver enzymes * Bone marrow/blood cell damage: anemias of red and white blood cells can occur if the drug(s) is toxic to the bone marrow. In other cases drug allergies can cause indirect destruction of blood cells without damaging the bone marrow. D. Drugs for PCP Bactrim/Septra, and sulpha o BACKGROUND A variety of side effects have been reported for these drugs. These adverse effects can be grouped into the 5 groups listed in section B. Generally, once patients stop taking Bactrim/Septra (B/S) symptoms of allergy/toxicity go away. Patients can be switched to intravenous pentamidine, the new drug Mepron(R) (atovaquone, 566C80) or several other drugs to complete anti-PCP therapy. o DESENSITIZATION Once the patient has recovered some doctors try to help them reduce their sensitivity to the offending drug. At first doctors may give them very small doses of Bactrim/Septra (sometimes in liquid form) and over a period of weeks gradually increase their dose until it reaches the strength needed for prevention or treatment. This process is called desensitization. Should allergic reactions occur, doctors may use Tylenol and the antihistamine Benadryl and prednisone to reduce symptoms. Desensitization will not work for every patient. A schedule for desensitization has already appeared in TreatmentUpdate 24. o WHO GETS ALLERGIES TO BACTRIM/SEPTRA Researchers in Australia have been working at predicting which of their patients will develop allergies to Bactrim/Septra. Unfortunately these allergies can happen at any stage of HIV infection and more accurate ways of predicting this are needed. In separate studies in the USA and Zaire, black patients seem to be less likely than white patients to have skin rashes and reactions to B/S. In patients with liver disease, B/S may decrease the ability of kidneys to remove AZT from the blood. Other researchers think that supplements of anti-oxidants such NAC may help reduce these allergic reactions. o OTHER SULPHA DRUGS Other drugs containing sulpha such as dapsone, sulfadoxine (Fansidar(R)) and Sulphadiazine can also cause adverse reactions in people with HIV infection. See the section on drugs for toxo for more information on Fansidar and pyrimethamine. People of color may also get more side effects when given dapsone than white people. E. Drugs for PCP Pentamidine Given by aerosol, injection or intravenously, this drug can cause: * painful inflammation of the pancreas gland (pancreatitis) * abnormally low or high blood levels of sugar Given intravenously, pentamidine can cause: * kidney toxicity * damage to the bone marrow * abnormally low levels of platelets * liver toxicity (detected by the presence of increased blood levels of liver enzymes) * irregular heartbeats Many of these symptoms clear when patients stop receiving the drug. Giving intravenous pentamidine slowly is supposed to make drastic changes in blood pressure less likely. F. Other drugs for PCP o CLINDAMYCIN * nausea * diarrhea (more common with oral clindamycin) * rash; the rash may go away after "3 to 5 days" even though therapy may be continued * Erythromycin may block the antibiotic effects of clindamycin o PRIMAQUINE * destruction of red blood cells (hemolysis) can happen in patients who do not produce enough of a certain enzyme (glucose-6-phosphate dehydrogenase). This may particularly affect people of color. * Methemoglobulinemia: a condition that results in less oxygen being made available to the body o MEPRON(R) This drug has only been recently introduced and experience with it is limited. Side effects reported include: * diarrhea G. Antifungal drugs o AMPHOTERICIN B (ORDINARY AND LIPOSOMAL FORMS) * fever * chills * nausea * kidney toxicity Drugs such as miconazole and ketoconazole, when given at the same time, may worsen damage to the kidneys and decrease the effectiveness of amphotericin B. As well, carbenicillin, digitalis and ticarcillin may interact with amphotericin B and cause the kidneys to malfunction. o FLUCONAZOLE In general, fluconazole is usually "well tolerated" by patients. None the less, some patients may experience: * nausea and/or vomiting * headache * rash * stomach pain and diarrhea can also be a problem Fluconazole may interact with several other drugs: Rifampin. This anti-TB drug may decrease the level of fluconazole in the blood. Some doctors suggest increased doses of fluconazole when patients are using rifampin Phenytoin. Blood levels of this drug increase when given to patients taking fluconazole o KETOCONAZOLE * nausea * vomiting When this antifungal is taken with food its absorption is decreased. Some doctors increase the dose given to patients with HIV infection because of low levels of stomach acid. Thus patients using the anti-ulcer drugs cimetidine (Tagamet(R)) or ranitidine (Zantac(R)) should not take ketoconazole at the same time as those other drugs. Rifampin. This antibiotic can significantly reduce blood levels of ketoconazole Hismanal(R)(astemizole) and Seldane(R)(terfenadine). These anti-allergy drugs interact with ketoconazole resulting in high blood levels of Hismanal or Seldane. This interaction can lead to heart problems and even death. o ITRACONAZOLE This antifungal appears to be "well-tolerated". Side effects include: * nausea * rash * vomiting * liver toxicity (particularly in patients who have hepatitis) Itraconazole can interact with several drugs and this interaction can kill patients: Hismanal (astemizole) and Seldane (terfenadine) can interact with itraconazole and cause heart problems leading to death. The following drugs can reduce blood levels of itraconazole-- cimetidine (and related compounds), isoniazid, phenytoin and rifampin. o FLUCYTOSINE * bone marrow toxicity * nausea and/or vomiting H. Drugs for toxo See the section on PCP for information on Bactrim/Septra, Mepron, Clindamycin, primaquine and sulpha drugs. o FANSIDAR This combination of pyrimethamine and Sulphadiazine can cause side effects in as many as 70% of patients. Such effects include: * severe and life-threatening rash * reduced levels of white blood cells and platelets * high blood levels of liver enzymes Fansidar may interact with AZT worsening bone marrow damage and possibly decreasing the anti-toxo effects of Fansidar. I. Drugs for MAC and TB Many of the standard drugs used to treat MAC and/or TB can have side effects particularly in people with HIV infection. Some of these side effects can be reduced and others cannot. As well, some of the side effects are similar to the symptoms of MAC infection (such as nausea and diarrhea). It is not always easy to separate the causes of these symptoms. o AZITHROMYCIN Licensed for the treatment of lungs infections, chlamydia and syphilis, it is recommended that azithromycin not be given to patients allergic to erythromycin and "related" antibiotics. Side effects can include * nausea * vomiting * diarrhea * stomach pain o Clarithromycin (see TreatmentUpdate 27, 40 and 42.) o CIPRO (ciprofloxacin) Common side effects: see side effects of azithromycin * seizures Antacids reduce absorption of Cipro. o Clofazimine * skin and urine may become discolored * Eyesight: long-term use of this drug may damage the retina decreasing vision. Some doctors suggest that patients taking this drug for long periods of time may need their vision monitored. o Ethambutol * Color blindness and blurred vision: patients taking more than 15 mg/kg of body weight/day can develop problems with vision. o Isoniazid Side effects include: * liver toxicity--increases with age and use of rifampin * pain, loss of sense of touch in the feet and hands (peripheral neuropathy), vitamin B6 supplements may reduce this problem * rash and nausea Using antacids will decrease the absorption of this drug. Isoniazid may also increase the body's need for vitamin B6. As isoniazid can affect how the liver processes drugs it may increase blood levels of Valium(R)(and related drugs) and phenytoin. o Rifampin * This drug can cause a "hypersensitivity syndrome" usually within 3 hours of taking the drug. The symptoms of this condition include "flushing, fever, redness of the eyes and [low levels of platelets]." * Orange discoloration of "urine, tears and sweat" can occur (this is not harmful) * liver toxicity (increases in blood levels of liver enzymes). Most of these symptoms appear within the first two months of using rifampin. Rifampin decreases the absorption of the following drugs: dapsone, methadone and ketoconazole (the Food and Drug Administration in the USA recommends that the two drugs should not be taken together). Fluconazole absorption is reduced by about 23% and rifampin users may need to take higher doses of fluconazole to deal with this problem. Aspirin and related drugs can reduce absorption of rifampin. o Pyrazinamide * severe joint pain * Liver toxicity has been described as "the most important side effect associated" with this drug. When large doses of pyrazinamide have been used (40 to 50 mg/kg/ day) this is more likely to happen. Pyrazinamide does not appear to increase liver toxicity when taken with isoniazid and rifampin. o Rifabutin * Bone marrow suppression * low levels of white blood cells called neutrophils * low levels of platelets. * orange staining (this is not harmful) of saliva, semen, stool, tears, urine * rash, gas and nausea * Liver enzyme levels in the blood may increase. As rifabutin is "related" to rifampin side effects and drug interactions seen with rifampin may also happen with rifabutin. J. Methadone and other drugs Used to help heroin and other narcotic users overcome their addiction, methadone can interact unfavorably with a number of drugs. This interaction can result in reduced blood levels of methadone and thus distressing withdrawal symptoms. Rifampin (600 to 900 mg/day) can reduce blood levels of methadone by 33% to 68%. This can also happen with reduced doses of rifampin-- 450 mg/day. Anti-seizure drugs such as phenytoin, carbamazepine and phenobarbital can all reduce blood levels of methadone Valium and "related" drugs can increase methadone blood levels Barbiturates, especially phenobarbital can reduce blood levels of methadone Methadone can reduce blood levels the anti-depressant desipramine The immune booster naltrexone significantly reduces the effects of methadone and narcotics. REFERENCES: 1. Lee BL and Safrin S. Drug interactions and toxicities inpatients with AIDS. Current Opinion in Infectious Diseases 1992;5(2):231 -240. 2. Lipsky JJ. Zalcitabine and didanosine. Lancet 1993;341:3032 3. Mepron. Product monograph 1993. 4. Azithromycin.Product monograph 1992. 5. Rifabutin. Product monograph 1993. WE NEED YOUR SUPPORT CATIE is the only community-based organization in Canada which is devoted to research on treatment information for HIV/AIDS. In addition to TreatmentUpdate/TraitementSida, we publish a bulletin on alternative therapies called The POSITIVE Side. CATIE is engaged in a number of research projects designed to help people with HIV infection. Our observational database (using MedLog(R)) study will provide information on the efficacy of a number of potential therapies. Our HookingUp report can be used to help people gain better access to social services. We are also planning a health promotion programme for people with HIV infection. All donations are tax-deductible Support us in the fight against AIDS. Make your cheque or money order for: $100 $50 $30 $20 $_____ payable to: CATIE 517 College Street, Suite 324 Toronto, Ontario M6G 4A2 Whatever your contribution, we would like to thank you for your support. Charitable Registration Number 0886697-13