Subject: Treatment Update #32 Date: Apr 1992 (760 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T U P D A T E && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TreatmentUpdate 32 By Sean Hosein -- April 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. AZT, HIV and the intestine B. AZT and interferon C. AZT, ddC, and interferon: NIH studies toxic effects II IMMUNOMODULATORS A. Thalidomide and ulcers III INFECTION FIGHTERS A. Digestive Tract problems and some solutions IV ANTI-CANCER AGENTS A. Hyperthermia for KS -- a phase I trial V TESTING A. Bio-rhythms found to affect interferon therapy B. Measuring triglycerides -- cheaper than interferon? ***** I ANTI-HIV AGENTS A. AZT, HIV, and the intestine Although people with HIV infection often lose weight as a result of persistent diarrhea or incomplete absorption of food, the administration of AZT can result in weight gains. Researchers in Berlin have recently investigated the intestinal complaints of 33 HIV-infected subjects in order to better understand the effect of AZT on the intestine The subjects had experienced persistent weight loss, diarrhea, stomach pains, nausea, and difficulty swallowing. Several portions of the intestine were examined for damage and lesions, and samples of intestinal tissue, as well as stool samples, were analyzed for parasites; none of the subjects had parasites or cancer. However, the researchers found a range of physical and biochemical changes in the intestines of the subjects. For instance, parts of the intestine were clearly damaged, which would likely have resulted in impaired absorption. As well, cells lining the intestine appeared to be dysfunctional and also physically malformed. Some white blood cell located in the intestines of these subjects were found to be infected with HIV. In some subjects, the growth of intestinal cells seemed to be out of control. Treatment with AZT appeared to improve intestinal function, at least in the short term. The researchers suggest that AZT's immunosuppressive effects on the development of intestinal cells normalized the growth of those cells. This is not very surprising; AZT is known to be toxic to the rapidly- dividing cells of the bone marrow. As cells of the intestine also experience rapid growth and development, it is likely that AZT would affect them. The researchers conclude that HIV- infected patients without cancer or intestinal infection can benefit from the "intestinal toxicity" of AZT. The precise dose of AZT used by the Berlin doctors was not given. REFERENCES: 1. Ullrich R, Heise W, Bergs C et al. Effects of Zidovudine treatment on the small intestinal mucosa in patients infected with the Human Immunodeficiency Virus. Gastroenterology 1992;102:1483-1492. ***** B. AZT and interferon Use of AZT (Azidothymidine, Retrovir, Zidovudine) for symptom-free patients is likely to delay the appearance of opportunistic infections and the loss of CD4+ cells, although large doses of AZT can cause toxicity. As yet, the optimal dose of AZT, by itself, or in combination with other agents, remains unknown. As the beneficial effects of AZT are known to wear off, physicians and their patients are experimenting with combinations of several anti-HIV agents, as well as with other drugs, which may help compromised immune systems. One such combination calls for AZT with interferon-` (IFN- `). Interferons can affect the immune system and also exert anti-viral activity. In experiments with cells and HIV, IFN-` has demonstrated anti-HIV qualities; in particular, IFN-` can reduce the production of virus in cells chronically infected with HIV. In contrast, AZT and similar drugs do not effectively suppress HIV production in chronically infected cells. Thus, some researchers think that AZT used with IFN-` may provide more effective therapy. As well, the anti-HIV effect of the two drugs together may allow for reduced doses of both agents, resulting in less toxicity. Several clinical trials of both agents have taken place. Such combinations have provided benefit to HIV-infected subjects with or without Kaposi's sarcoma, at least in the short term. In one study, researchers at the Karolinska Institute in Stockholm gave IFN-` (3 million units/day), along with AZT (400-1200 mg/day), to 18 subjects with symptoms of HIV infection. Although results suggest a reduction in virus production, the combination produced toxic side effects, greater than would have been seen with AZT alone. Indeed, use of IFN-` appeared to cause a decrease in CD4+ cell counts. In a more recent study, researchers in the USA have conducted experiments on subjects with HIV infection using AZT and IFN-`. The study enrolled 13 subjects with AIDS/ARC and fewer than 250 CD4+ cells. No subject had an opportunistic infection or cancer at the time of entering the study. Subjects were given AZT initially at 1200 mg/day, reduced as necessary, for 6 weeks, to suppress the level of HIV replication. Eventually, at least half the subjects were taking AZT at a dose of 600 mg/ day. IFN-` was given in various doses ranging from 1.25 million units to 7.5 million units three times per week. Fragments of an HIV protein called p24 are produced when the virus is replicating; detection of p24 is an indirect measure of HIV replication. However, there are several problems in relying on p24 to gauge viral replication, and the test came under heavy criticism during the VII International Conference on AIDS in Florence for not providing an accurate picture of viral replication. One senior scientist with the LCDC (Laboratory Centre for Disease Control, Ottawa) told TreatmentUpdate that p24 antigen tests are useful in determining if infants have HIV infection, but apart from that, the test is of little value in evaluating the effect of therapy on disease progression in HIV- infected patients. This is in part because the sensitivity of the test is low; it is estimated that half the people with HIV infection who have viral replication test "negative" for p24 antigen. It is hoped that third generation test kits have the potential to be of greater use, although even "acidification" of samples does not always improve the sensitivity of the test. By the third month of combination therapy, there were significant reductions in the level of p24 detected. After this point, statistically significant increases in the level of p24 in 11 of 12 subjects were seen, despite use of both AZT and IFN-`. "No consistent change" was reported in the levels of ~2- microglobulin. During the first 10 weeks of the study, CD4+ counts fell at the rate of approximately 7 cells/week. The higher the dose of IFN-` administered, the greater was the reduction in CD4+ cell counts. This finding was statistically significant. The researchers said that the reduction in CD4+ counts occurred because IFN-` caused bone marrow suppression which in turn caused a fall in the total lymphocyte count. As a percentage of the total lymphocyte count, the percentage of CD4+ cells remained the same. Two subjects developed PCP during the study. No other life-threatening infections/ cancers were reponed. There may be several reasons to account for the failure of AZT and IFN-` in these subjects. One possible answer is that these subjects had advanced HIV infection, and that their immune systems were too weak to take advantage of the therapy. Another possible answer is that subjects may have been unable to respond to IFN-` because the cells of the immune system may have become insensitive to the drug. This has been reported by other research teams, and is one of many abnormalities which occur in people with HIV infection. The presence of interferon inhibitors is perhaps another reason why dismal results were seen in this trial. Such inhibitors may include anti-IFN antibodies and/or other substances. A possibility not mentioned by the researchers is that the increasing toxicity over time of AZT and IFN-` may have played a role in the lack of efficacy seen in this study. After several months, the anti-HIV effect of IFN-` seemed to wear off. Indeed, increasing the dose of IFN-` did not reduce viral replication. All in all, the researchers "found no evidence of lasting impact on viral or immunologic markers after IFN-` therapy in [subjects] with advanced HIV infection already receiving [AZT]." They report, "Further study of the escape from antiviral effects after 2 to 4 months of therapy may lead to better strategies for optimizing and prolonging any benefits achievable with this regimen. For the present, the addition of interferon therapy appears to offer little advantage over Zidovudine alone in patients with advanced HIV-I infection." REFERENCES: 1. Berglund O, Engman K, Ehrnst A et al. Combined treatment of symptomatic Human Immunodeficiency Virus Type 1 infection with native IFN-` and Zidovudine. Journal of Infectious Diseases 1991:163:710-715. 2. Edlin BR, Weinstein RA, Whaling SM et al. Zidovudine Interferon-` combination therapy in patients with advanced Human Immunodeficiency Virus type 1 infection: Biphasic response of p24 antigen and quantitative polymerase chain reaction. Journal of Infectious Diseases 1992;165:793-798. 3. Weber J and Ariyoshi K. Lack of correlation between acidified HIV p24 antigen and plasma viraemia. AIDS 1992;6(4):428429. 4. Turano A, Balsari A, Viani E et al. Natural human antibodies to `-interferon interfere with the immunomodulatory activity of the lymphokine. Proceedings of the National Academy of Sciences USA 1992;89:4447-4451. C AZT, ddC, and interferon; NIH studies toxic effects As mentioned in the previous article, the beneficial effects of AZT and interferon-` (IFN-`) therapy appear to wear off after several months, at least in subjects with advanced HIV infection. Several possible explanations were produced by the study investigators. One hypothesis not fully examined was the combined toxicities of the 2 drugs. Researchers at the National Institutes of Health (NIH, Bethesda, Maryland) who specialize in the study of drug toxicity have begun to investigate the potential for toxicity of nucleoside analogues such as AZT and ddC, as well as interferon-`. The scientists performed experiments on white blood cells, as well as on mice given doses of IFN-` equivalent to between 2 million to 400 million units of interferon. Four important results were obtained. First, is that the number and function of lymphocytes were reduced over the short-term (1 to 10 days). Second, as exposure to IFN-` continued beyond the short-term, toxicity to lymphocytes was reduced. Third, exposure to IFN-` reduced the ability of T and B cells to coordinate their response to foreign organisms. Fourth, the separate toxicities caused by IFN-` and nucleoside analogues did not reinforce each other's toxicities. Overall, the immune suppression caused by chronic exposure to IFN-` was moderate. However, the researchers warn that some "specific lymphocyte-associated functions are found to be dramatically suppressed," and suggest that such toxicity may render control of HIV infection more difficult. REFERENCES: 1. Saunders VM, Powell-Oliver FE, Rosenthal GJ et al. Immune-associated toxicities induced by in vivo and in vitro exposure to Interferon alone or in combination with nucleoside analogues. International Journal of Immunopharmacology 1991;13 (supplement 1):109-115. ***** II IMMUNOMODULATORS A. Thalidomide and ulcers In the late 1950's the drug thalidomide was licensed in several countries, but after the appearance of malformed babies born to women who had taken the drug while pregnant, the drug was banned. Now, however, it may have a role to play in combatting certain complications arising from HIV infection. Infection by the mycobacteria which cause leprosy can bring about a variety of responses from the immune system. If the response by T-cells is weakened, inflammations can appear in the eyes, kidneys, joints, and elsewhere. Painful nodules in the skin can also occur. This collection of symptoms/signs is called ENL (erythema nodosum leprosum). In double-blind trials, thalidomide brought about improvement in subjects with ENL. The drug has no antibiotic activity, and it is thought that its beneficial effects are a result of its interaction with the immune system. Thalidomide has been used in Graft versus host disease (GVHD), an immunologic disorder with some similarities to AIDS. GVHD can develop in patients receiving transplanted organs/tissues. Patients who are scheduled to receive transplants must take some form of immunosuppressive therapy so that the transplanted tissue can survive. Patients with GVHD are thought to have received cells from the immune system of the donor which triggers an immune reaction against the recipient's tissues. If this process happens immediately after transplantation, it is known as acute GVHD. In such cases, cells of the skin, liver, and gastrointestinal tract come under attack, resulting in skin rashes, jaundice, and diarrhea. Sometimes the skin or cells lining the gut "may simply slough off." As many as 60% of patients who get GVHD can die, despite immunosuppressive therapy. GVHD can also become a chronic condition. Thalidomide can cause improvement in as many as 50% of patients with chronic GVHD, but only in one in seven with acute GVHD. Thalidomide has been reported to cause the healing of oral and throat ulcers in patients with HIV infection. Such ulcers are usually not caused by bacteria, viruses or, fungi, but rather by the immune system's attacking the body. Doses of between 50 to 200 mg/day have been administered, and improvement occurred within 2 weeks. A side-effect of thalidomide can be damage to nerves, which has been reported in at least 2 HIV patients who had been taking the drug over long periods of time. In one case, the drug was prescribed at doses of 100 mg/day for 6 months. In the other case, 50 mg twice/week was prescribed for 7 months. The patients recovered once they stopped taking the drug. A recent review article suggests that thalidomide should not be given to HlV-infected patients who also have peripheral neuropathy or obvious brain dysfunction. As well, some doctors suggest that the drug should be used only in patients who do not respond to other forms of therapy. Another way to reduce the possibility of neuropathy is to use short courses of the drug instead of continuous doses. Although thalidomide has not been reported to cause declines in CD4+ cell counts, it seems clear that it interacts with the immune system in ways which have yet to be understood. REFERENCES: 1. Gunzler V. Thalidomide in Human Immunodeficiency Virus (HIV) patients: a review of safely considerations. Drug Safety 1992;7(2):116-134. 2. Math G, Meyer P, Brienza S et al. Retrospective study correlating clinical infectious history and peripheral blood T- cell subpopulations in cancer, GvH, and HIV+ patients. Biomedicine and Pharmacotherapy 1992;46: 17-19. 3. Dalgleish AG, Wilson S, Gompels M, et al. T-cell receptor variable gene products and early HIV-I infection. Lancet 1992;339:824-828. ***** III INFECTION FIGHTERS A. Digestive tract problems and some solutions At some time during the course of their illness, people with HIV infection may experience gastrointestinal problems. Symptoms can include difficulty and pain while swallowing, painful ulcers, and diarrhea, and determining their cause is sometimes difficult because there may be more than one organism causing the symptoms, or in some cases, no apparent infectious cause. For patients having difficulty swallowing, examination of the throat is often useful, and most cases, the commonest cause of problems is yeast infection. It should be noted, however, that yeast infection can occur without producing symptoms. In many cases, ketoconazole (200 to 400 mg/day) or fluconazole (100 to 200 mg/day) generally results in a decrease in symptoms. Absorption of ketoconazole depends on acidic conditions in the stomach, and patients with HIV infection do not always have enough stomach acid for optimal absorption. Administering small doses of hydrochloric acid or vitamin C should improve absorption of ketoconazole. If patients do not improve, despite use of ketoconazole or fluconazole, then some physicians recommend low- dose Amphotericin B. Should this fail, some doctors order X-rays of the throat and/or other affected areas while the patient is given radioactive dyes. Sometimes the drug thalidomide can reduce the severity of ulcers. As well, some patients taking ddC can also develop ulcers; when they stop taking it, the ulcer often heals. Another procedure which may help some doctors in making a diagnosis is to collect samples from esophageal brushing. Patients are given a local anesthetic for the throat, and a tube is inserted in the mouth and down the throat. At the end of the tube, a small brush is extended, and then as the tube is withdrawn, the brush comes into contact with the esophagus. The brushings can later be examined for fungus. This technique is said to be highly effective for diagnosing yeast infections. Using an endoscope to view affected parts of the tube connecting the throat to the stomach (esophagus) is sometimes useful as well. After Candida, the next most common cause of gastrointestinal problems is infection with herpes viruses such as herpes simplex virus (HSV) and cytomegalovirus (CMV). These viruses can cause ulcers. In such cases, acyclovir, ganciclovir, or foscarnet may help. If the ulcer heals, the drugs can be withdrawn and the patient monitored for relapse. Other doctors suggest continuous reduced doses of one of these three drugs, to prevent the reappearance of ulcers. Ulcers may also be caused by HIV, and some doctors find that treatment with corticosteroids may be beneficial. Mycobacteria such as those that cause tuberculosis have been found to also cause inflammation in the digestive tract. Combination therapy with several antibiotics may help relieve symptoms. Kaposi's sarcoma (KS) tumours can also block the throat and affect the gastro-intestinal tract. Although lymphoma can affect the gastro-intestinal tube between the stomach and the throat, it is rare. Some doctors recommend radiation therapy for such complications. Another common problem for people with HIV infection is diarrhea. Ganciclovir has been useful for CMV colitis. There is some controversy over maintenance therapy with this drug. As in cases of CMV retinitis, damage caused by the virus will recur unless maintenance therapy is given. The risk/benefit analysis is some times difficult to resolve for patients with CMV colitis. Maintenance doses of ganciclovir will likely decrease the recurrence and spread of the infection, but on the other hand, risks include bacterial infection of catheters used to infuse the drug, as well as immune-suppressive effects. Infection with C. parvum can be another cause of diarrhea. A review of some therapies used to treat this infection is found in TreatmentUpdate #26. Other parasites such as microsporidia can cause diarrhea. Albendazole (to be reviewed in TreatmentUpdate #34) and metronidazole have been reported to reduce the need for anti-diarrheal agents. Another parasite, Isopora belli, can also cause diarrhea. High doses of Bactrim/Septra, or of pyrimethamine (75 mg/day) with the B- vitamin folic acid (to reduce the bone marrow toxicity of pyrimethamine) are helpful in resolving the infection. Another microorganism which can cause diarrhea is C. difficile because continuous use of various antibiotics can change the balance of bacteria living in the intestine, resulting in the growth of unwanted bacteria and yeasts. In some cases, withdrawal of antibiotics stops the diarrhea. Doctors may also prescribe the antibiotic vancomycin (125 to 500 mg 4 times daily for 10 to 14 days). Another drug is metronidazole 250 mg 4 times per day. In TreatmentUpdate #29 we reported on the use of a "friendly yeast" for the treatment of AIDS-related diarrhea. Doctors can also prescribe agents which are not antibiotics. Narcotics such as opium, morphine, and codeine can be used, although there is a risk of addiction. Lomotil and imodium slow the movement of food through the intestine. Some doctors find that doses in excess of the maximum daily dose are sometimes required to "control severe diarrhea." Fiber absorbs water and reduces the water content of the stool. Some doctors have found Metamucil (in doses of 1 to 2 tablespoons in a glass of water twice per day) useful in controlling mild cases of diarrhea. Other agents, including Octreotide (Sandostatin), lithium, and enkephalins are under investigation. REFERENCES: 1. Simon D, Weiss LM, and Brandt L. Treatment options for AIDS-related esophageal and diarrheal disorders. American Journal of Gastroenterology 1992;7(3):74-281. 2. Wilcox CM. Esophageal disease in Acquired Immunodeficiency Syndrome: Etiology, diagnosis, and management. American Journal of Medicine 1992;92:412-421. ***** IV ANTI-CANCER AGENTS A. Hyperthermia for KS -- phase-I trial Removing blood from the body, heating it, and then reinfusing it back into the body (hyperthermia) has been used as a therapy for several cancers. Heating tumours may also make them more susceptible to chemotherapy. Almost two years ago, researchers in the USA reported that hyperthermia may benefit patients with Kaposi's sarcoma. In an experiment on 3 subjects with KS, hyperthermia therapy resulted in the disappearance of KS lesions for at least 1.5 years in one individual. In a second subject with many KS lesions in his lungs, some improvement was seen, although one month after therapy, lesions had regrown. The third subject, despite "significant lesion regression", later died. Researchers in Italy have began a study to observe the effects of hyperthermia in subjects with KS. Ten subjects with KS were enrolled at Clinica Citta di Pavia, in Pavia, for this study. Of the ten, eight subjects had KS skin lesions in several places. Of these eight, six also had KS tumours in various organs. One subject had KS restricted to a lymph node. The diagnosis of KS was confirmed by doctors at another medical facility. All potential subjects for this study had small samples of tumours removed for testing. These tumours were subjected to heat in experiments to make sure that heat treatment would not increase their growth. In 8 subjects, CD4+ counts were fewer than 60 cells. Two subjects had more than 400 CD4+ cells. In all subjects, high levels of neoptrin and ~2-microglobulin were present, and thus it was likely that these subjects had high levels of acid-labile interferon as well. Under a general anesthetic, blood was removed via catheters, and circulated through a water bath where its temperature was raised to 47x (Celsius). The heated blood was then pumped back into the subjects. The core body temperature of the subjects was raised to 42x. Attempts to minimize heat loss through use of blankets or aluminum foil were not successful, and the core body temperature did not rise above 42x. Researchers continued this procedure for one hour. The study protocol required only one course of hyperthermia. As a result of hyperthermia, all subjects who had hairy leukoplakia experienced its complete disappearance. In one, leukoplakia returned 3 weeks after hyperthermia. This subject also had some KS lesions disappear, while others grew. Those subjects with CMV retinitis did not experience worsening symptoms. In 4 subjects, "fever blisters" appeared, suggesting activated herpes infection. Several hours after hyperthermia had ended, KS lesions on mucus membranes and in the lungs rapidly disappeared. In one subject, all KS lesions disappeared; his complete remission lasted for 4 months (no further data available). In 7 subjects, a partial reduction in the number and extent of lesions was noted. For 5 of these subjects, tumour regression persisted for more than 2 months. In the other 2 subjects, tumours began to reappear after one month. Analysis of study data suggests that response to hyperthermia is likely to be greater in subjects with relatively high numbers of CD4+ cells. Hyperthermia resulted in significant increases in the CD4+ cell count in the 2 subjects who had pre-study values greater than 400 cells. Those subjects who had pre-study counts fewer than 400 CD4+ cells before hyperthermia, did not experience significant changes in their cell count. In all subjects, levels of p24 antigen, interleukin-2, neoptrin, and ~2- microglobulin fell after hyperthermia. No "evidence of HIV...stimulation" was seen by the researchers. No subjects died as a result of hyperthermia. In laboratory experiments, heat treatment (more than 42x) has been shown to directly damage tumours. Hyperthermia has been shown to destroy the network of blood vessels created by tumours. As well, hyperthermia also affects the immune system, and causes changes in production of interferons and interleukins. Heat treatment can cause the destruction of HIV-infected cells. Moreover, HIV is also rendered inactive by temperatures above 37x. In laboratory experiments, exposure to a temperature of 42x over a period of 2 hours resulted in almost 100% inactivation of large quantities of HIV. In experiments conducted under the aegis of the NIAID, heat treatment of HIV-infected cells resulted in increased viral replication. However, 90% of HIV-infected cells in that study were killed when the temperature was raised to 45x. Heating HIV-infected cells above 42.7x or below 41.5x in those experiments did not result in increased viral replication. The Italian researchers think that further studies using hyperthermia ought to be conducted. REFERENCES: 1. Alonso K, Pontiggia P, Nardi C, et al. Systemic hyperthermia in the treatment of HIV-related Kaposi's sarcoma. A phase I study. Biomedicine and Pharmacotherapy 1992;46:21-24. ***** V TESTING A. Bio-rhythms found to affect interferon therapy A daily bio-rhythm (circadian rhythm) has been noted in humans as well as in animals. Changes in hormones and in the immune system occur during the day and night over a 24-hour period. Circadian rhythms may even be strong enough to affect the growth of tumours and infections. Researchers in France (Villejuif and Paris) have conducted experiments on cancer patients who were considered unlikely to recover despite anti- cancer therapy. The researchers found that circadian rhythms may have a powerful effect on patients' response to therapy and thus, on their survival. Ten adult subjects (without HIV infection), of whom 6 had previously "failed" cancer therapy, were enrolled in the study. All subjects had kidney tumours which had spread to other parts of the body. Their chances of survival were considered to be remote. Subjects were given a small pump which released interferon-` (IFN-`) into the blood at different rates, depending on the time of day. Most of the IFN-` was released between 6pm and 10pm. Subjects started with 15 million units of IFN-`/m2 of skin surface for 21 days. Between 6am to 10am the pump released the least amount of IFN. Natural killer cells (NK) are an important part of the immune system's anti-cancer defenses. The timing of the drug's delivery was designed to maximize the exposure of NK cells to IFN-`. Between 6pm to 10pm, NK cells are responsive to IFN-`. Also at this time, the body is less susceptible to toxic effects of IFN-`. To decrease side effects of IFN, subjects were allowed up to 3 grams of acetaminophen (Tylenol) per day. Use of INF-` was allowed until it became too toxic or the subjects' disease progressed. In most subjects, fatigue was a common side-effect as the dose of IFN was increased. Other toxic signs/symptoms common to IFN such as fever, mental confusion, decreased blood counts (as a result of bone marrow suppression) were seen. However, all of these disappeared "within 10 days after discontinuing [IFN-`]." Only 7 subjects could be evaluated for anti-cancer effects of the drug, as the remaining 3 died. In 4 subjects, tumours either did not increase in size, or spread to other sites. Prior to IFN-` use, in these 4 subjects, tumours had been increasing in size. A large decrease in bone pain as well as in improvement in the ability to move was seen in 2 subjects. Of the 7 survivors, at least half were monitored for 15 months. At least half of the survivors experienced a stabilization in their condition for 10 months. Two subjects continued to use IFN for over 10 months. None of the subjects produced anti-IFN-` antibodies. As expected, IFN-` caused statistically significant decreases in lymphocytes as well as in CD4+ and CD8+ cell levels during IFN-` administration. When IFN was stopped after the 21st day, these blood values increased. By contrast, the percentage of NK cells (as a percentage of lymphocytes) increased with IFN- `. When results from this study were compared to another in which IFN was administered in the usual manner, side effects such as the flu-like syndrome and nausea appeared to be "much less severe" in the group given IFN depending on the time of day. The reduction in the number of lymphocytes during IFN-` administration is thought to occur because the bone marrow retained those cells and delayed their release. Once administration of IFN-` stopped, blood cell values returned to normal. No opportunistic infections occurred as a result of IFN-a therapy in the latest French study. Further trials of IFN-` using this novel schedule are planned for other subjects with cancer. As IFN-` is used by some patients with HIV infection, perhaps clinical trials of this schedule may minimize toxic effects. REFERENCES: 1. Depres-Brummer P, Levi F, DiPalma M, et al. A phase I trial of 21-day continuous venous infusion of at-interferon at circadian rhythm modulated rate in cancer patients. Journal of Immunotherapy 1991;10(6):440447. ***** B. Measuring triglycerides -- cheaper than interferon? Infection by bacteria, viruses, and parasites results in a series of complex reactions from the immune system. Such infections can also affect the way the body processes food, as well as alter energy cycles. Researchers in Amsterdam have documented some of these changes. According to their research, these changes in energy cycles and metabolism happen shortly after a person is infected with HIV. (See TreatmentUpdate #29) Triglycerides are lipids used by the body to construct various fats. Researchers have noted that people with HIV infection produce larger-than-normal quantities of triglycerides. It is thought that under the stimulation of cytokines such as interferon and interleukin as well as TNF (tumour necrosis factor), the liver's production of triglycerides and fats is increased. Researchers in San Francisco have been studying the relationship between cytokines and triglycerides in subjects with HIV infection. The researchers studied 75 male subjects, some of whom had AIDS, while others were HlV-infected, but free of symptoms. A group of non-HIV-infected and healthy subjects was used as a control. The doctors found that subjects with HIV infection who did not have symptoms had higher-than-normal levels of triglycerides. The subjects with AIDS also had elevated triglyceride levels. The differences in triglycerides between those with HIV infection and those without were found to be statistically significant (not due to chance alone). Subjects with AIDS also had elevated blood levels of interferon-` compared with those in the control group. Only a small number of the HlV-infected but symptom-free subjects had elevated blood levels of interferon-`. None of the control subjects had detectable levels of interferon-` in his blood samples. This relationship was statistically significant. No statistically significant comparisons could be made comparing values among the different groups of subjects for body cell-mass (to detect weight loss), TNF, and interleukin-1~. Precisely why subjects with HIV infection have elevated triglyceride levels which increase with worsening immunodeficiency is not fully understood. Some researchers have suggested that there may be a relationship among elevated interferon-`, TNF, and the wasting syndrome in HIV-infected subjects. In other infections and certain conditions such as diabetes, elevated triglyceride levels have also been found. In experiments with interferon, liver cells have increased triglyceride production. In one study with healthy, non-HIV- infected subjects, injections of IFN-` have not resulted in increased blood levels of triglycerides. But that study was not done for a long period of time. In subjects with HIV infection who are constantly producing IFN-`, as has been documented in several studies, perhaps higher triglyceride levels are a result of stimulation with IFN-a. Experiments with cells and animals suggest that long term IFN~ administration has the potential for raising triglyceride levels. In further work, the San Francisco doctors have found that injection drug users who were HIV-infected but symptom-free had elevated triglyceride levels. In contrast, HIV-infected but symptom-free gay men had normal levels of triglycerides. The latest research report from these doctors found that abnormalities in the way the body processes cholesterol occur early on in the course of HIV infection, long before high levels of triglycerides and IFN-a are detected. The effects of decreased blood levels of cholesterol early on in HIV-infected people is unknown. According to the study researchers, "many patients with AIDS show stable weight despite profound disturbances in lipid metabolism." They also add that elevated levels of triglycerides and IFN-` may not necessarily "be linked to wasting." By studying triglycerides, IFN-`, and cholesterol production, the researchers hope to find out what causes these metabolic abnormalities. In this way, it is hoped that the wasting seen in some patients with advanced HIV infection can be halted. Measurement of triglycerides could be used as a "surrogate marker" (along with CD4+ cells, ~2-microglobulin, and neoptrin) to test the effectiveness of therapies for HIV infection. As well, since the presence of IFN-` in the blood of people with HIV infection often appears before the development of life-threatening infections and/or cancers, triglyceride measurements -- like those of acid-labile INF-` -- hold the possibility of alerting doctors to which of their patients are at risk of disease progression. REFERENCES: 1. Grunfeld C, Kottler DP, Shigenaga JK et al. Circulating interferon levels and hyper triglyceridemia in the Acquired Immunodeficiency Syndrome. American Journal of Medicine 1991;90:154-162 2. Grunfeld C, Pang M, Doerrler W et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in Human Immunodeficiency Virus infection and the Acquired Immune Deficiency Syndrome. Journal of Clinical Endocrinology and Metabolism 1992;74(5):1045-1042. ***** 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. 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