Subject: Treatment Update #31 Date: Mar 1992 (905 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T U P D A T E && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TreatmentUpdate31 By Sean Hosein March 1992 ISSN 11817186 --------------------------------------------- Community AIDS Treatment Information Exchange Reseau Communautaire D'info-Traitements SIDA --------------------------------------------- CONTENTS: [items are separated by "*****" for this display] I ANTI-HIV AGENTS A. Passive immunotherapy for HIV B. Discoverer of HIV studies passive immunotherapy II IMMUNOMODULATORS A. DHEA for diarrhea? B. Disappearing T-cells C. Autoimmunity: clues for treatment D. Interferon: more than just an antiviral E. Acid-labile interferon F. Interferon as problematic G. Interferon: predicting illness H. Reducing excessive interferon with naltrexone I. Reducing excessive interferon with AZT III INFECTION FIGHTERS A. Clarithromycin -- interactions with food IV TESTING A. Looking for MAC B. DHEA: predicting AIDS Permission granted for noncommercial reproduction on condition that direct quotations are cited. ***** I ANTI-HIV AGENTS A. Passive Immunotherapy for HIV Transferring protective antibodies from people already immune to an infectious agent to people who have no resistance to that agent has been done for several infections. Such therapy (passive immunotherapy) is also effective in immunosuppressed patients such as those who have received transplants. It is thought that people with HIV who are otherwise symptom-free may be better able to keep the virus under control as compared to people with advanced HIV infection. One possible explanation is that symptom-free patients produce large quantities of antibodies which can neutralize HIV. Initially, people infected with HIV produce antibodies which attack several viral proteins. The outer coat or envelope of the virus has proteins labelled gp160 and gp120. The inner region or core of the virus has proteins called p17 and p24. During the first few years after infection, levels of antibodies against p24 as well as the envelope proteins remain relatively high. Some researchers think that antibodies produced against the core proteins may be more effective in controlling the virus than antibodies directed against envelope proteins. As symptoms develop and immune dysfunction worsens ,production of antibodies against p24 begins to decline. The transfer of protective antibodies from symptom-free patients to those who have symptoms has resulted in reduced infections and improved quality of life. ***** B. Discoverer of HIV studies passive immunotherapy Working in the laboratory of Dr. Luc Montagnier at the Institut Pasteur (Paris, France), Dr. Francoise Barr-Sinnousi in 1983 was the first to isolate the virus that would later be called HIV. She has continued to study compounds which inhibit the replication of HIV. Dr. Barr-Sinnousi, together with other doctors in Paris, France, is conducting research with passive immunotherapy on people with HIV infection. Initial studies suggest that passive immunotherapy may help people infected with HIV, even those with severe immunodeficiency. Eighteen subjects with AIDS were enrolled into the study. None of these subjects had more than 100 CD4+ cells; nor did any have any active opportunistic infections at the time they entered the study. These subjects received blood from one of two groups of donors described below. One group of donors consisted of 9 HIV-infected but symptom-free individuals. The average CD4+ count of the donors was above 400 CD4+ cells. Every 4 weeks 600 ml of blood was taken from each of the donors. The other group of donors (56 people) were not infected with HIV or the hepatitis B virus. Their blood was used as a control and was given to half of the subjects in the study. The portion of blood which has antibodies is known as the plasma. Blood rich in antibodies against HIV was frozen and later heat-treated to inactivate HIV. A toss of the coin decided which of the 18 subjects received plasma from HIV-positive or HIV-negative donors. Nine subjects received plasma from HIV- positive donors and the remaining 9 subjects received plasma from the HIV-negative donors. Plasma was transfused for 20 minutes every 2 weeks. Each subject received 7 infusions of plasma (over a period of 14 weeks) and 500 mg/day of AZT. If toxicity to AZT developed, it was withdrawn and given in reduced doses and later raised back to 500 mg/day. All subjects received aerosolized pentamidine for prevention of PCP. Among the HIV-infected but symptom-free donors no adverse changes were detected as a result of donating blood. The average CD4+ count of the donors remained more-or-less the same. All the recipients in the study tolerated the donated plasma. One subject who received HIV-positive plasma died of the wasting syndrome and infection by CMV. One subject receiving HIV-negative plasma also died. There were no significant differences between the two groups of subjects when use and doses of AZT were evaluated. Both groups had 1 subject who developed Kaposi's sarcoma. Changes in CD4+ cell counts and weight between the 2 groups of subjects were not statistically significant during the study. The number of life-threatening infections was greater in the group receiving HIV-negative plasma (8 infections) compared to the group receiving HIV-positive plasma (2 infections). This difference was statistically significant; that is not likely due to chance alone. In subjects who received HIV-positive plasma, the level of viral replication appeared to have fallen "dramatically" according to the study investigators. The Karnofsky score is a measure of the physical capacity of people to perform activities needed for everyday life. This measure declined significantly between weeks 14 and 34 among those who had received HIV-positive plasma. After week 20, subjects who had received HIV-positive plasma showed severe deterioration; developing fevers, weight loss and reduced levels of platelets. Transfusions of HIV-positive plasma were reintroduced in week 34 for subjects who had previously received them. In some subjects there was a noticeable improvement; in others none. Three subjects died despite reintroduction of HIV-positive plasma during weeks 34 to 42. By the 17th month after the start of the study only 2 subjects were still alive, both of whom were receiving transfusions of HIV-positive plasma from symptom-free donors. The study doctors concluded that use of plasma from HIV- positive but symptom-free donors provides benefit; subjects receiving such plasma have fewer opportunistic infections. The doctors also noted that when this plasma was withdrawn subjects appeared to have a large increase in viral replication with "...a severe deterioration of clinical status...not related to opportunistic infections." These doctors have began a double- blind, randomized study with 90 subjects receiving plasma for 1 year. In this second trial, if the beneficial effects are confirmed, it is expected that getting a large enough supply of helpful antibodies to meet demand will become a problem. One potential solution for this problem is to try and produce such antibodies through laboratory techniques. REFERENCES: 1. Vittecoq D, Mattlinger B, Barr-Sinoussi F et al. Passive immunotherapy in AIDS: A randomized trial of serial Human Immunodeficiency Virus-positive transfusions of plasma rich in p24 antibodies versus transfusions of seronegative plasma. Journal Infectious Diseases 1992;165:364-368. ***** II IMMUNOMODULATORS A. DHEA for diarrhea? Infection with the parasite C. parvum can cause life threatening diarrhea in HIV-infected patients. People who are receiving immune suppressive therapy (such as those receiving transplanted organs) can also experience diarrhea caused by this parasite. When the immune suppressive agent is withdrawn patients often recover. This suggests that the use of immunomodulators may help patients infected with C. parvum. Researchers at Utah State University have performed a variety of experiments with rats and DHEA (dehydroepiandrosterone) in order to clarify its role as a potential therapy. Rats were given corticosteroids to suppress their immune systems and were then infected with C. parvum. Use of DHEA appeared to reduce the severity and spread of C. parvum infection compared with rats not given the drug. Damage to the intestines of the rats because of inflammation arising from the infection was reduced in those animals receiving DHEA. The exact mode of DHEA's protective action from the damage caused by C. parvum infection remains unknown. One theory is that the drug may affect the growth of microorganisms living in the intestine. A more likely explanation is that DHEA may have helped restore some immune function(s) necessary for controlling the infection. Experimental results from the rat model of immune suppression do not always mean that results in humans with HIV infection will be the same. The American scientists do, however, suggest that DHEA has potential as a possible treatment of C. parvum infection in humans. In experiments in Italy, doctors have found that the use of an immune booster with antibiotics to be superior to antibiotics alone when treating diarrhea in people with HIV infection. Hopefully, controlled trials will help clarify the potential of DHEA for use against C. parvum infection. An analogue of DHEA called EL- 10 is under development by the Elan corporation, Athlone, Ireland. REFERENCES: 1. Rasmussen KR, Arrowood MJ, Healy MC. Effectiveness of dehydroepiandrosterone in reduction of cryptosporidial activity in immunosuppressed rats. Anti-microbial agents and chemotherapy 1992;36(1):220-222. ***** B. Disappearing T-cells Significant loss of helper T-cells and abnormal CD4/CD8 ratios eventually develop in humans infected with HIV. Initially, infection of CD4+ cells by HIV was thought to be the sole cause of their decline. Recent research suggests that HIV does not infect enough CD4+ cells to directly account for their decline. There may be other, perhaps indirect, ways which could account for the huge loss of CD4+ cells. Several theories have been put forward to explain the decrease in CD4+ cells. There is some experimental evidence for each of the following theories: o fusing of HIV-infected CD4+ cells with uninfected cells to form large clusters called syncytia; o cofactors such as mycoplasma or other microorganisms may also "assist" HIV in destroying CD4+ cells; o autoimmunity; exposure to HIV could trick the immune system into attacking CD4+ cells and other components of the immune system; and/or o superantigens; a variation on the autoimmune theory. Superantigens are proteins produced by viruses or bacteria which cause an enormous stimulation of the immune system, which eventually attacks itself. This last explanation is novel and has generated intense interest among researchers in Europe as well as in Montreal (Dr. JP Routy, personal communication). Researchers at NIAID (National Institute of Allergy and Infectious Diseases) have found that a virus which causes an AIDS-like condition in mice instructs infected cells to produce a superantigen. Thus it is possible that HIV-infected cells could also produce a superantigen. REFERENCES: 1. Groux H, Monte D, Bourrez J-M et al. L'activation des lymphocytes T CD4+ de subjects asymptomatiques infects par le VIH entrame le declenchement d'un programme de mort lymphocytaire par apoptose. Compte Rendus de L'Academfe des Sciences 1991;312(III):599-606. 2. Marx J. Clue found to T cell loss in AIDS. A "superanligen" encoded by the AIDS virus may cause the progressive immune cell depletion that leads to the collapse of patients' immune systems. Science 1991;254:798-800. ***** C. Autoimmunity: clues for treatment Some researchers have found similarities between the effects of HIV infection on humans and disorders where the immune system attacks itself, a condition known as autoimmunity. Examination of autoimmune disorders might lead to improved treatments for complications of AIDS. This has already been the case with the platelet disorder ITP (Idiopathic thrombocytic pupurea) where the number of platelets is reduced. In non-HIV- infected subjects use of the drug dapsone is useful in treating ITP. This has encouraged researchers to test dapsone on people with HIV-related ITP, where it has been found to provide benefit. Another example is the drug danazol, a weakened male hormone -- which has also been useful for non-HIV-related ITP. As that drug has been found to normalize CD4/CD8 ratios, it may also be helpful for people with HIV infection. In exploring autoimmunity further, researchers have found another similarity between autoimmune disorders and HIV infection. It appears that people with HIV infection produce excessive amounts of an unusual form of interferon. Precisely why HIV-infected people develop suppressed immune systems despite producing anti-viral antibodies against HIV and supposedly protective substances such as interferon is uncertain. In this issue of TreatmentUpdate we examine research on interferon, its production in people with HIV infection and potential treatments for helping the immune system to correct the dysfunction arising from HIV infection. REFERENCES: 1. Edelman AS and Zolla-Pazner S. AIDS: a syndrome of immune dysregulation, dysfunction, and deficiency. Federation of American Societies for Experimental Biology Journal 1989;3:22-30. ***** D. Interferon: more than just an antiviral Proteins such as interferons and interleukins are known as cytokines. Interferon (IFN) has a broad range of effects; it can affect anti-cancer cells, antibody producing B-cells and also cause the production of other cytokines. As IFN can affect many cells in a variety of ways, dysfunction within the IFN system may cause disturbances in other parts of the immune system. There are reports of disturbances in immune function with several autoimmune disorders including rheumatoid arthritis, hepatitis B, diabetes, immune deficiencies, multiple sclerosis and Lupus (SLE: systemic lupus erythematosus). Defects of the IFN system in these disorders have been noted to involve both IFN alpha and gamma. Often the highest levels of IFN in the blood are found when the severe episodes of autoimmune diseases occur. In experiments with mice who have an autoimmune disorder, injections of IFN seem to worsen the disorder and shorten lifespan. Thus, it is even possible that IFN itself may be the cause of some of the immune dysfunction in autoimmune disorders. This may also be the case in lupus. The defects in the immune system of people with Lupus include: (1) increased blood levels of IFN alpha; (2) a decreased sensitivity to the effects of IFN; and (3) a reduced ability to produce IFN. REFERENCES: 1. Interferon-alpha regulation of lymphocyte function in systemic Lupus erythematosus. Sibbitt WI, Froelich CJ and Bankhurst AD. Clinical Immunology and Immunopathology 1984;32:70-80. ***** E. Acid labile Interferon In the early 1980's researchers in the USA were already noting similarities between AIDS and autoimmune diseases. Two examples of similarities are ITP -- a platelet disorder -- and the presence of a certain type of interferon (IFN) in the blood of people with AIDS. One of the earliest studies found abnormalities of the immune system among its subjects. In testing the volunteers, researchers found that in 91 cases IFN was detected in the blood of subjects with symptoms of HIV infection (persistently swollen lymph glands and Kaposi's sarcoma). When these results were compared to a group of healthy subjects, the presence of IFN in symptomatic subjects was statistically significant, that is, not likely due to chance alone. It was found that this IFN was damaged by exposure to acidic conditions, thus it was described as acid-labile. Viral infections usually cause the immune system to produce large quantities of IFN. At first it was thought that infection with CMV(Cytomegalovirus) or EBV (Epstein Barr Virus) was the cause of IFN production in people with symptoms of what would later be called AIDS. A comparison among subjects who were infected with herpes viruses such as CMV and EBV and those who were not infected found that infection with those viruses did not necessarily result in IFN production. Previous studies have shown that tumor cells can stimulate the immune system into producing IFN. As IFN was found in subjects without KS or other cancers among the group of 91 subjects noted earlier, it seemed unlikely that tumors would be the sole cause of IFN production. The doctors conducting the study said that it was not clear if IFN was a cause or consequence of the dysfunctional immunity seen in their subjects. REFERENCES: 1. DeStefano E, Friedman RM, Friedman-Kien AE et al. Acid labile human leukocyte interferon in homosexual men with Kaposi's Sarcoma and lymphadenopathy. Journal of Infectious Diseases 1982;146(4):451-455. 2. Pitha PM. Multiple effects of interferon on HIV-l replication. Journal of Interferon Research 1991;11:313-318. ***** F. Interferon as problematic Interferons were first thought to be proteins which protected cells from attack by viruses. As a result of further research it is now known that interferons have a range of properties which include regulating the immune system as well as affecting cell growth and development. There are 3 basic types of interferon; alpha, beta and gamma. As well, there are many sub-types; some of which are affected by acid (acid-labile) and others which are not (acid-stable). It is thought that under normal conditions, there is a balance among the various sub-types of IFN. In certain autoimmune disorders, such as rheumatoid arthritis, Lupus and also in AIDS, the type of IFN produced is usually acid-labile. Healthy people do not normally have IFN in their blood and the continuous production of acid-labile IFN seen in autoimmune disorders may be harmful. Some researchers think that acid-labile IFN disrupts communication between cells of the immune system resulting in increased production of certain hormones and cytokines and decreased production of others. Interestingly, IFN-alpha is similar to a group of compounds called endorphins. Endorphins are used by the brain and the immune system for communication. IFN-alpha is not only similar to endorphins but can act like one as well; mimicking their effects. In experiments with mice IFN- alpha interacts with brain cells and binds to receptors designed for pain relief and messenger molecules. This IFN can also act like a hormone; it increases the production of steroids by the adrenal glands. IFN-alpha also interacts with insulin as well as the thyroid gland. As there are links between the brain and the immune system, disturbances involving IFN-alpha, such as acid- labile IFN-alpha, are likely to have an effect on the brain as well. Over the long-term, these abnormalities involving IFN- alpha may pose a more serious problem for the brain as well as the immune system. REFERENCES: 1 . Surkovich S, Skurkovich B and Bellanti JA. A unifying model of the immunoregulatory role of the interferon system: can IFN produce disease in humans? Clinical Immunoloa and Immunopathology 1987;43:362-373. 2. Wiedermann CJ, Sacerdote P, Mur E et al. Decreased immunoreactive beta-endorphin in mononuclear leukocytes from patients with rheumatic diseases. Clinical and Experimental Immunology 1992;87:178-172. ***** G. Interferon as a predictor of illness The high level of acid-labile IFN found in the blood of certain people with HIV may actually be a sign of worsening immune dysfunction. Researchers in New York measured the blood levels of IFN in over 100 subjects with signs/symptoms of suppressed immune systems as a result of HIV infection. Generally subjects who were symptom free or had minor infections had a higher level of IFN compared with people without HIV infection. Subjects with Kaposi's sarcoma or AIDS had even higher levels of IFN. It was noted that 5 subjects with the highest levels of IFN developed AIDS within 2 to 17 months after their IFN was last measured. Doctors in Israel have also found that high levels of IFN also appear to herald the appearance of opportunistic infections. These findings raise questions about the suitability of IFN as a treatment for some people with HIV infection. Other researchers at Sloan-Kettering in New York have examined various laboratory markers for their ability to predict survival in subjects with AIDS or Kaposi's sarcoma These researchers gave 70 subjects various doses of IFN-alpha (Roferon-A made by Hoffman-La Roche), some as high as 54 million units per day. At intervals of 2 to 4 weeks subjects were observed for any changes in their health. Subjects given large doses of IFN were more likely to exhibit reductions in the size of tumors. Forty-two percent of subjects later developed an opportunistic infection. Tests of immune function showed that those subjects with better immune function were less likely to develop an opportunistic infection. At least 1/2 of the subjects were followed for 17 months. At the time of analysis of the study data, 53% of evaluable subjects were dead. Analysis showed that subjects who responded to IFN-alpha had statistically significant improved survival compared with "non-responders". The factor most associated with survival was the absence of IFN- alpha in the blood of subjects before therapy. Over 60% of subjects in this trial had elevated levels of interferon which was acid-labile. Subjects with this IFN had a poor tumor response to IFN-alpha injections. As well, subjects with acid- labile IFN also had reduced survival compared with subjects without this type of interferon. In another study 43 subjects with HIV infection and KS were followed for their response to combined treatment with IFN-alpha and AZT. In this study, the best predictor of survival was the level of Beta2-microglobulin; the lower the level of Beta2- microglobulin the better the chance of survival. The 2nd best predictor of survival was the absence of IFN in the blood of subjects. Low levels of neopterin were also associated with survival. That Beta2 microglobulin and neopterin were associated with survival is not really surprising as both are produced by cells stimulated with IFN. Measurement of acid-labile IFN is usually a procedure done in certain research labs. However, test kits for neopterin and Beta2-microglobulin are easier to use and more readily available. REFERENCES: 1. Vadhan-Raj S, Wong G, Grecco C et al. Immunological variables as predictors of prognosis in patients with Kaposi's sarcoma and Acquired Immunodeficiency Syndrome. Cancer Research 1986;46:417-425. 2. Levin S, Hahn T, Handzel ZT et al. Activated Interferon system in healthy homosexual men. Antiviral Research 1985;5:229- 240. 3. Krown SE, Niedzwiecki D, Bhalla RB et al. Relationship and prognostic value of endogenous interferon-alpha, Beta2- microglobulin, and neopterin serum levels in patients with Kaposi's sarcoma and AIDS. Journal of Acquired Immunodeficiency Syndromes 1991;4:871-880. ***** H. Reducing excessive interferon with Naltrexone In summary, research done in the past decade makes it clear that only some patients with HIV infection may obtain benefit from interferon (IFN). These "responding" patients are likely to have relatively high CD4+ cell counts and an intact immune system. They are also likely to have low blood levels of Beta2- microglobulin and neopterin and thus none or very low levels of acid-labile IFN. The use of IFN in people with HIV infection is controversial. For some subjects with Kaposi's sarcoma (KS) the drug appears to cause a reduction in the amount and size of skin lesions, a least in the short-term. Results from one small, controlled study suggest that IFN injections in symptom-free subjects may even reduce the incidence of opportunistic infections compared with similar subjects who received a placebo. Unfortunately this trial cannot be described as being truly double-blind since the subjects who received IFN reported severe symptoms of a "flu-like" syndrome. These symptoms could hardly be expected from an inactive placebo. The acid-labile IFN produced by people with HIV infection appears before the onset of worsening symptoms. This form of IFN may be more than just a warning sign; acid-labile IFN seems likely to do damage to the immune system in different ways. First, this interferon activates the TNF system in the body (Tumor necrosis factor: a protein used by the body to destroy cancer cells). The continuous activation of the TNF system appears to make cells of the immune system more sensitive to toxins produced by bacteria. This can result in T-cells destroying themselves. Moreover, by increasing production of TNF, acid-labile IFN indirectly causes increased HIV replication. A dysfunctional TNF system is thought to play a role in the wasting syndrome seen in some patients with AIDS. Second, prolonged production of acid-labile IFN may upset the IFN component(s) of the immune system. This can result in the body producing substances which inhibit the production and activity of IFN. Such IFN inhibitors have been found in the blood of patients with advanced HIV infection. As "normal" IFN is essential in the control of infections and cancer, it is unclear what the mixture of acid-labile IFN and IFN-inhibitors in the blood of patients with HIV infection means. Some research suggests that acid-labile IFN has the ability to convert"normal" IFN into the acid-labile form. This raises questions about the suitability of therapy with interferons over the long-term in people with HIV-infection. Third, the presence of acid-labile IFN may, over the long- term, disrupt communication networks between the immune system and the brain. High levels of acid-labile IFN could be responsible for some of the neurological complications seen in advanced HIV infection. As well, the coordination between the brain and immune system -- needed for proper control of infections -- may be weakened by the continuous stimulation of acid-labile IFN. Suppressing the production and activity of acid-labile IFN alone is unlikely to "cure" people with HIV infection. However, the results from 2 controlled trials using different drugs do suggest that subjects who can reduce their levels of acid-labile IFN may experience improved quality of life and survival. In the mid-1980's Dr. Bernard Bihari and others in New York conducted a double-blind trial of naltrexone (at a dose of 1.75 mg/day) in people with AIDS. Thirty-eight subjects were given naltrexone or placebo for 3 months. At the end of this time subjects on placebo were switched to naltrexone. Subjects receiving naltrexone had fewer infections compared with subjects on placebo during the first 3 months. Twenty-five of 38 subjects eventually had a reduction in their blood levels of interferon (IFN). This gradual reduction in the blood levels of IFN sometimes took as much as 12 months to occur. All 13 subjects whose IFN levels did not decrease died within 9 months. Four years after the trial 10 of the 25 (40%) responding subjects were still alive. Nine of the 10 "were still working full time and are essentially symptom-free" according to Dr. Bihari. The average CD4+ cell count has remained the same and their immune functions appear to have improved. Dr. Bihari now uses naltrexone together with other immuno- modulators -- such as cimetidine (Tagamet) and Antabuse -- as well as prophylaxis against infections as part of a treatment regimen. Patients are also advised to develop a programme of nutritional support. Naltrexone is made in the USA by DuPont and sold under the brand name of 'Trexan'. Although it is not licensed in Canada, like several other drugs it is available through Canada's Emergency Drug Release Programme (EDRP). Taken at bed time in a solution of syrup at a dose of 2.75 mg/day, naltrexone seems not to cause serious side effects. Normally, the drug is given in much higher doses (50 mg/day) to help people recover from addiction to heroin. Even at those doses it has not caused serious adverse reactions. Project Inform has published instructions for mixing naltrexone with syrup to ensure that the right concentration is made. REFERENCES: 1. Ambrus JL, Poiesz BJ, Lillie MA et al. Interferon and interferon inhibitor levels in patients infected with varicellazoster virus, Acquired Immunodeficiency Syndrome, Acquired Immunodeficiency syndrome-related complex, or Kaposi's sarcoma, and in normal individuals. American Journal of Medicine 1989;87:405-407. 2. Lau AS, Der SD, Read S et al. Regulation of tumor necrosis factor receptor expression by acid-labile interferon- alpha from AIDS sera. AIDS Research and Human Retroviruses 1991;7(6):545- 552. 3. Szebeni J, Dieffenbach C, Wahl SM et al. Induction of alpha interferon by Human immunodeficiency virus type 1 in human monocyte-macrophage cultures. Journal of Virology 1991;6362- 6364. 4. Sanders VM, Powell-Oliver FE, Rosenthal GL et al. Immune-associated toxicities induced by in vivo and in vitro exposure to interferon-alpha alone or in combination with nucleoside analogues. International Journal of Immunopharmacology 1991:13 (Supplement 1):109-115. 5. Wiedermann CJ, Sacerdote P, Mur E et al. Decreased immunoreactive beta-endorphin in mononuclear leukocytes from patients with rheumatic diseases. Clinical and Experimental Immunology 1992;87:178-172. 6. Holan V, Nakamura S and Minowada J. Inhibitory versus stimulatory effects of natural human interferon-alpha on proliferation of lymphocyte sub- populations. Immunology 1992;75:176-181. 7. Tyor WR, Glass JD, Griffin JW et al. Cytokine expression in the brain during the Acquired Immunodeficiency Syndrome. Annals of Neurology 1992;31:349-360. 8. Ginzburg HM and MacDonald MG. The role of Naltrexone in the management of drug abuse. Medical Toxicology 1987;2:8392. 9. Bihari B, Drury F, Ragone V et al. Low dose naltrexone in the treatment of AIDS. IV International Conference on AIDS, Stockholm, 1988; abstract 3056. 10. Cotton P. Immune boosters disappoint AIDS researchers. Journal of the American Medical Association 1991;266(12):1613- 1614. 11. Anonymous. Project Inform fact sheet on Naltrexone. Project Inform 1987. ***** I. Reducing excessive interferon with AZT For several years anecdotal reports from New York City have suggested that patients given AZT often have reduced blood levels of acid-labile interferon (IFN) as a result. A data analysis of a double-blind, placebo- controlled study (conducted in the mid 1980's) in the USA suggests that subjects receiving high dose AZT had statistically significant reductions in their blood levels of interferon and triglycerides compared with subjects assigned to placebo. Although the ability of cells to activate AZT into its antiviral state appears to wear down after 3 months of continuous use, the drug's ability to suppress the production of interferon (see TreatmentUpdate 26) is thought to provide benefit, at least in the short-term. The significance of triglyceride levels and their association with disease progression in people with HIV infection will be discussed in TreatmentUpdate 32. REFERENCES: 1. Mildvan D, Machado SG, Wilets I and Grossberg SE. Endogenous interferon and triglyceride concentrations to assess response to Zidovudine in AIDS and advanced AIDS-related complex. Lancet 1992;339:453-456. 2. Bass HJ, Hardy WD, Mitsuyasu RT et al. The effect of Zidovudine treatment on serum neopterin and Beta2-microglobulin levels in mildly symptomatic, HIV type I seropositive individuals. Journal of Acquired Immune Deficiency Syndromes 1992;5(3):215-221. 3. Hutterer J, Armbruster C, Wallner G et al. Early changes of neopterin concentrations during treatment of Human Immunodeficiency virus infection with Zidovudine. Journal of Infectious Diseases 1992; 165:783-784. ***** III INFECTION FIGHTERS A. Clarithromycin -- interactions with food The relatively new antibiotic clarithromycin has recently been licensed in the USA. As the drug can kill many types of organisms including mycoplasma, N. gonorrhoeae, Chlamydia and MAC (mycobacterium avium complex), it is likely to be useful for people with HIV infection. Absorption of drugs taken orally can be affected by the presence or absence of food. For instance, the absorption of AZT is reduced if that drug is taken with meals. Researchers at Abbott laboratories in the USA have been conducting experiments on humans to investigate the behaviour of clarithromycin. The 28 humans used in these studies did not have HIV or any other infection. The researchers found that taking the drug within 1/2 an hour after eating a meal increased the absorption by 25%. Abbott labs has said that such an increase "...is minor and should be of limited clinical significance...". However, some of the populations in which the drug is going to be used are unlikely to be in the same state of good health as the subjects in this study. As disseminated MAC infection generally occurs in people with less than 100 CD4' cells a 25% increase in blood levels of this antibiotic, may, over the long term, have a beneficial effect. Six subjects reported side effects such as "stomach ache or cramps...diarrhea ...and headache." All of these side effects were described as "mild" by the investigators. The opinions of the subjects experiencing these symptoms were not stated. REFERENCES: 1. Chu S-Y, Park Y, Locke C et al. Drug-food interaction potential of clarithromycin, a new macrolide antimicrobial. Journal of Clinical PharmacoloD 1992;32:32-36. IV TESTING A. Looking for MAC Before the 1980's DMAC (disseminated Mycobacterium Avium Complex) infection was relatively rare in North America. As the number of people diagnosed with AIDS increased so did disseminated MAC infection. At first many doctors were not unduly concerned about the appearance of MAC in their patients; doctors did not think that MAC infection actually worsened their patient's health. As well, in the early years of the epidemic there was no effective therapy for MAC infection. The development of antibiotics such as azithromycin, clarithromycin, rifabutin and sparfloxacin makes effective treatment and prevention of MAC infection much more likely. Thus patients with disseminated MAC infection should be identified as quickly as possible. Doctors in Atlanta, Georgia have conducted a review of the hospital records of 972 patients with AIDS between 1985 and 1990. Of the 972 patients, 16% or 155 had DMAC. This diagnosis was based on finding MAC in blood, bone marrow or liver samples. There were no significant differences in the proportion of people developing DMAC when categories such as "sex, race" and "risk factor" were used. There were, however, differences when the category "age" was used. The highest incidence of DMAC was seen in people aged 20 to 29 years old. In looking at lab tests which correlated with a diagnosis of MAC the researchers found that cases of DMAC occurred in people with less than 100 CD4~ cells. Anemia, involuntary weight loss, diarrhea and high levels (more than 3 times the normal upper limit) of the liver enzyme alkaline phosphatase were all statistically significant variables associated with DMAC in people with less than 100 CD4+ cells. People who used AZT and anti-PCP drugs did not have a reduced incidence of DMAC compared with people who did not use those agents. As in a previous study, younger people appeared to have a higher incidence of DMAC. Exactly why this happens is unclear. Although not statistically significant, night sweats and persistently swollen spleens appeared to be associated with DMAC. As the symptoms of DMAC are similar to disseminated CMV, salmonella or histoplasmosis, perhaps a larger study may have clarified the association of DMAC with those signs and symptoms. No cases of symptom-free DMAC were found by the Atlanta doctors. These doctors suggest testing for DMAC in any patient with a CD4 count of less than 100 cells and any of the following: involuntary weight loss, elevated Alkaline phosphatase, anemia and/or diarrhea. REFERENCES: Havlik JA, Homsbaugh CA, Metchock B et al. Disseminated Mycobacterium avium complex infection: clinical identification and epidemiologic trends. Journal of Infections Diseases 1002;165:577-580. ***** B. DHEA: predicting AIDS An important hormone produced by the body is DHEA (Dehydro- epiandrosterone). A small study which measured DHEA in HIV- infected subjects suggested that levels of this hormone declined as immune dysfunction worsened. Researchers in Amsterdam have recently completed a study on a large number of HIV-infected subjects; their results also indicate that a relation between DHEA and immune deficiency exists. Two hundred and thirty-eight initially symptom-free subjects were followed for 5 years. Over time, a number of subjects developed AIDS and data on 41 of these subjects were compared with data from subjects who did not progress to AIDS. Initially, both the group that developed AIDS and the group that did not had similar blood levels of DHEA. As the study progressed, the average DHEA blood level among subjects who developed AIDS fell to a level lower than among those who did not develop serious infections and/or cancers. This difference in the DHEA levels between the 2 groups was statistically significant. Data generated in this study suggests that DHEA levels begin to decline in people shortly after they become infected with HIV. According to the data analysis, people with DHEA levels below 7 nmol/litre are at high risk for the development of AIDS. It was noted that subjects with initially low levels of DHEA seemed more likely to develop cancer compared with subjects with initially higher levels of DHEA. Although this is at least the third study to find a relationship between blood levels of DHEA and worsening immune deficiency, exactly why this happens is uncertain. It is thought that the impaired functioning of the adrenal glands in HIV infection may be the cause of declining output of DHEA. Production of this hormone decreases with age and appears to have a range of immune-enhancing effects in laboratory experiments with cells. In addition to increasing production of the T-cell growth factor IL-2 (interleukin 2), DHEA protects mice from otherwise lethal infections. DHEA has weak anti-HIV activity on some HIV-infected cells. It is not surprising that DHEA levels were lower in those subjects who developed cancer because experiments with cells and animals suggest that the drug has a protective effect against cancer. The test kits for DHEA are sold by Diagnostic Products, Los Angeles and the cost of measuring DHEA is less than the cost of CD4+ cell counts and p24 antigen tests. The study authors caution that a single DHEA measurement by itself is probably of little value. However, declining test values over a period of time are likely to be of greater significance for people with HIV infection. Whether or not anti-HIV drugs such as AZT or ddI cause DHEA levels to rise (or fall) is not known. DHEA and its sulphated form (DHEA-sulphate) are absorbed orally and have been given to humans for years as a treatment for various disorders. Doses as high as 1600 mg/day have been taken without serious toxicity. The drug is licensed in Japan and Italy and is available from selected buyers clubs in the USA. REFERENCES: 1. Mulder JW, Frissen PHJ, Krijnen P et al. Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic Human Immunodeficiency Virus men. Journal of Infectious Diseases 1992;165:413-418. ***** 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