TreatmentUpdate 72 By Sean Hosein Volume 8, no 8 October 1996 A publication of the Community AIDS Treatment Information Exchange (CATIE). Table of Contents I IMMUNOMODULATORS A. At last, a sensible, safe dose of IL-2 II INFECTION FIGHTERS A. Adefovir (GS 840) for hepatitis B B. AmBisome(R) for fungal infections in the brain C. Low-dose fluconazole to prevent crypto D. Lamisil(R) looks good in the lab E. Bone marrow stimulant and Humatin(R) for diarrhea F. Women using fluconazole G. Therapies for CMV H. Cidofovir in the eye --- once every 6 weeks III TESTING A. Absorbing more itraconazole by taking it with food B. Patients in hospitals may not get their medicine C. Saquinavir levels reduced by rifabutin D. Survival decreases under managed care A word to readers In this issue, we complete our presentation of results from the 36th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). Since much of the information is from abstracts, we may not be able to provide readers with the details that normally accompany our reports. Researchers did not release the long-term results of many of the studies. I IMMUNOMODULATORS A. At last, a sensible, safe dose of IL-2 Background IL-2 is a chemical produced by the immune system which stimulates the growth of T cells and helps them fight infections. Most studies testing IL-2 in PHAs have used large doses -- millions of units per day. At those doses IL-2 causes side effects including:  fever  muscle and bone pain  tiredness  headache Now a group of American researchers have tested low dose of IL-2 and we present their results. Study details Doctors at the New York-Cornell Medical Center recruited 16 HIV-infected subjects (the gender of the subjects was not released) with an average of 347 CD4+ cells. The subjects had been infected with the virus for an average of 7 years. All subjects had to use at least one of the following anti-HIV drugs AZT, ddC, ddI, d4T and 3TC for a minimum of 1 month before receiving IL-2. Researchers gave the subjects different doses of IL-2 in an attempt to find a nontoxic dose. Results -- toxicity and HIV The researchers found that the highest range of doses subjects could tolerate before side effects developed was 187,500 to 250,000 IU/square metre of skin/day. Moreover, subjects were able to use the drug for six months, without developing side effects. Production of HIV was not significantly affected when subjects used IL-2 at or below this range of doses. Results: Boosting the immune system The type of immune response needed to fight many of the infections seen in AIDS is called CMI (cell-mediated immunity). There are no cheap, sophisticated tests to measure CMI so researchers must rely on crude skin tests. Small amounts of protein from microbes (bacteria, fungi and viruses) are injected under the skin. If CMI is intact, within 48-72 hours swelling and redness develop at the injection site. This reaction is called DTH (delayed-type hypersensitivity). In people with weak CMI the reaction is smaller and sometimes there may be no reaction.  Low-dose IL-2 Three of six subjects receiving 125,000 IU/m2/day or less of interleukin 2 whose skin did not react to testing before they received IL-2 , developed DTH reactions to fungi. This indicates that their immune system detected the fungus and was able to mount a response to attack it.  High-dose IL-2 Among those subjects who could tolerate doses of IL-2 ranging between 187,500 IU and 250,000 IU/m2/day, four of 10 subjects developed DTH reactions after 6 months of IL-2. Moreover, the size of the skin reactions were on average, double the size of pre-IL-2 reactions. This difference was statistically significant, that is; the increase was likely due to the dose of IL-2 used rather than luck.  NK cells Use of IL-2 did not cause increases in the level of CD8+, neutrophils and other cells with the exception of NK (natural killer) and, in some subjects, CD4+ cells. NK cells attack tumours and virus-infected cells. Subjects receiving the high dose IL-2 had their level of NK cells increase to 6 times higher than their pre-study level.  CD4+ cells Those subjects receiving 125,000 IU/day had their CD4+ count fall to an average of 276 cells which is about a loss of 28 CD4+ cells/month. Among subjects receiving up to 250,000 IU/m2 the average CD4+ cell count rose to an average of 543 cells or an increase of 28 cells/month. The differences in changes in CD4+ cell counts between the high and low dose groups was statistically significant. What's next? Large studies are needed to find out if the daily doses of IL-2 used in this study can:  delay the appearance of AIDS  decrease the risk of death when used in combination with other anti-HIV agents such as indinavir, nelfinavir, ritonavir, saquinavir and VX-478. REFERENCES: 1. Jacobsen EL, Pilaro F and Smith KA. Rational interleukin-2 therapy for HIV-positive individuals: daily low doses enhance immune function without toxicity. Proceedings of the National Academy of Sciences 1996;10405-10410. II INFECTION FIGHTERS A. Adefovir (GS 840) for hepatitis B Background Gilead Sciences which makes the anti-CMV drug cidofovir is also developing a treatment called adefovir (Bis-POM PMEA) for hepatitis B infection. Although most people quickly recover from HBV (hepatitis B virus) infection, a few develop continuous (chronic), low-level HBV infection in the liver. Over time HBV infects more liver cells and the damage slowly spreads through the entire organ. Eventually the liver damage is so severe that some people die and others get liver cancer. Doctors rely on interferon alpha to treat HBV infection but this drug is not always useful. Study details Doctors enrolled 20 subjects with chronic HBV infection into this study. Sixty-five percent of them also had HIV infection. Doctors randomly selected 15 subjects and gave each, one tablet of adefovir (125 mg) daily and 5 other subjects fake adefovir, both for 1 month. Results Levels of HBV fell by 97% compared to their pre-study level in subjects receiving adefovir. Subjects receiving fake adefovir had their level of HBV rise by 7% during the study. This difference in HBV levels between the two groups of subjects was statistically significant. This means that the changes in HBV levels were likely due to the use of adefovir and not a chance event. Toxicity Two subjects using adefovir had nausea while three had higher than normal levels of liver enzymes in their blood ; which indicated mild liver damage. HBV infection can also cause increases in liver enzyme levels. In other studies, nearly 200 HBV-infected people have used adefovir 125 mg/day for up to 14 months "without any sign of toxicity." In the US, adefovir is also being tested with AZT and related drugs as well as protease inhibitors as a treatment for HIV infection. REFERENCES: 1. Gilson RI, Chopra K, Murray-Lyon I, et al . Adefovir dipivoxil (Bis-POM PMEA) treatment for chronic hepatitis B infection; a placebo-controlled phase I/II study. Abstract LB01. 2. Anonymous. Gilead Sciences announces statistically significant antiviral activity against hepatitis B virus. Press release 16 September, 1996. B. AmBisome(R) for fungal infections in the brain Background One of the life-threatening brain infections PHAs can develop is 'crypto' (Cryptococcal meningitis). Standard treatment is iv AmB (amphotericin B) followed by oral fluconazole as maintenance. AmB can be toxic for the kidneys so researchers have been developing new forms of AmB one of which is called AmBisomer. This product consists of tiny balls of fat called liposomes containing amphotericin B. In theory these liposomes should penetrate the areas infected with the fungus and release the amphotericin there rather than expose the whole body to the drug. Study details Doctors in Amsterdam enrolled 28 HIV-infected subjects who had crypto into their study to compare the effects of AmB against that of Ambisome. Fifteen subjects received AmBisome 4 mg/kg of body weight per day for 3 weeks while 13 received AmB 0.7 mg/kg/day also for 3 weeks. After this both groups received oral fluconazole 400 mg/day for 7 days. Results Three subjects in each group did not recover during the first 3 weeks of the study. By the end of the 3rd week of the study technicians could not find any fungus in 10 of 15 subjects on AmBisome and in 3 of 8 subjects on AmB. This difference between the two groups was statistically significant, that is, likely due to the effects of the drugs rather than luck. Two subjects receiving AmB had to be withdrawn from the study because of kidney damage. Although the overall effects of AmBisome sound promising, more details are needed about the subjects in the study and their survival over the long term. REFERENCES: 1. Leenders ACAP, Reiss P, Portegies P, et al . A randomized trial of liposomal amphotericin B (AmBisome) 4 mg/kg versus amphotericin B 0.7 mg/kg for cryptococcal meningitis in HIV-infected patients. Abstract L035. C. Low-dose fluconazole to prevent crypto Study details Doctors in the US recruited 231 HIV-infected subjects, half of whom had 40 CD4+ cells, to test the ability of fluconazole to prevent the life-threatening brain infection crypto. Although none of the subjects had crypto in the past, 60% had experienced other life-threatening infections before entering this study. Subjects were supposed to take fluconazole 200 mg, three times daily, each week. Half the subjects were monitored for one year. Results During this time only 1 person developed crypto and 20% had yeast infections appear in the mouth or throat. The researchers interviewed subjects and found that the yeast infections were more likely to occur in subjects who did not take fluconazole as instructed. Among those subjects who did take fluconazole according to schedule, those that developed yeast infections had a "low" CD4+ cell count (the researchers did not release a figure). Only about 3% of subjects reported side effects -- "nausea [and] skin rash." REFERENCES: 1. Singh N, Barnish MJ, Berman S, et al . Low dose fluconazole for primary prophylaxis of cryptococcal infection confined to AIDS patients with less than 101 CD4+ cells: demonstration of efficacy in a prospective, multicentre trial. Abstract I173. D. Lamisil(R) looks good in the lab Background Lamisil (terbinafine) is a new antifungal drug licensed for treating fungal infections of the nails. As more reports of fungal infections resistant to fluconazole or itraconazole appear, doctors are beginning to consider combination antifungal therapy . In lab experiments, terbinafine used with fluconazole had greater antifungal activity than either drug alone in 50% of tests using yeast resistant to fluconazole. Even greater antifungal activity was seen in 90% of tests using itraconazole and terbinafine. Now experiments on HIV-infected people are needed to find out if the combination is safe and effective. REFERENCES: 1. Fothergill AW, Leitner I, Meingasser JG, et al . Combination antifungal susceptibility testing of terbinafine and the triazoles fluconaozle and itraconazole abstract E053. E. Bone marrow stimulant and Humatin(R)for diarrhea Background Infection with the parasite C. parvum can cause life-threatening diarrhea in PHAs. Doctors have tried many drugs to treat people infected with this parasite, including azithromycin, garlic enemas, paramomycin (Humatin) but use of these drugs do not work in every PHA. There have been a number of reports about the drug nitazoxanide but the details have not been published (see TreatmentUpdate 70). As well, none of these drugs deal with the underlying problem -- a weakened immune system. GM-CSF The chemical GM-CSF (granulocyte macrophage-colony-stimulating factor, also called Leukine(R)or Prokine(R)) is produced by the body and can stimulate the bone marrow to produce more white blood cells. It is used to treat people who have low levels of white blood cells because of chemotherapy, AZT or ganciclovir. It is possible that this bone marrow stimulant may also enhance the infection-fighting abilities of white blood cells. Study details Doctors in Milan have tested different drugs to try and help 2 PHAs with less than 50 CD4+ cells recover from diarrhea caused by C. parvum. The two had been treated with Humatin 4.3 grams/day for "at least 10 days" but their diarrhea did not resolve. The doctors then gave them GM-CSF -- 300 micrograms/day injected under the skin, for 14 days. They continued to receive paramomycin and AZT 500 mg/day. Results Recovery from diarrhea occurred in two days after the PHAs received GM-CSF. When the doctors stopped giving them GM-CSF the diarrhea returned and required several courses of GM-CSF (each course consisted of GM-CSF 300 mcg/day for 14 days). In one subject diarrhea disappeared and he has not had to use GM-CSF and Humatin for 6 months. The other subject's diarrhea decreased but never cleared. His condition gradually grew worse and he died 9 months after he began to use GM-CSF. Although these are only 2 cases, there is no effective treatment for the diarrhea caused by C. parvum and perhaps a pilot study with GM-CSF in other people with the same infection may confirm the drug's benefit or that of the related chemical G-CSF (granulocyte colony-stimulating factor). REFERENCES: 1. Capetti A, Bonfanti P, Rizzardini G, et al . Can rHu-GM-CSF help in treating drug-resistant cryptosporidiosis in AIDS? Abstract G033. 2. Barsig J, Bundschuh DS, Hartung T, et al . Control of fecal peritoneal infection in mice by colony-stimulating factors. Journal of Infectious Diseases 1996;174(4):790-799. 3. Lejeune M, Sariban E, Cantinieux B, et al . Defective polymorphonuclear function in children receiving chemotherapy for cancer are partially restored by recombinant human granulocyte-colony stimulating factor in vitro. Journal of Infectious Diseases 1996;174(4):800-805. F. Women using fluconazole Study details Doctors in the US recruited 323 HIV-infected women who had less than 300 CD4+ cells for this study. One hundred and sixty-two received fluconazole 200 mg/week and 161 received fake fluconazole (placebo). Researchers monitored 50% of subjects for 2 and a half years. Results Thirteen subjects developed yeast infections; 6 in the fluconazole group and 7 in the placebo group. REFERENCES: 1. Vasquez JA, Steel-Moore L, Schuman P, et al . Antifungal susceptibility among Candida species recovered from HIV-positive women receiving fluconazole prophylaxis. Abstract LB10. G. Therapies for CMV Who will get CMV retinitis? In North America, PHAs who have less than 50 CD4+ cells are at high risk for the development of CMV retinitis but not everyone with such a low cell count gets retinitis. Several research teams are developing tests to detect CMV in the blood of PHAs. Just as increasing levels of HIV in the blood (HIV viral load) is linked to wakened immunity, some doctors think that increasing levels of CMV in the blood may occur before signs of retinitis appear. Unfortunately reliable, accurate and rapid results from test kits for CMV viral load are not yet available. What the eyes see CMV can infect the light-sensing part of the eye called the retina, causing it to become swollen. People with HIV/AIDS who have CMV retinitis may see:  floaters  flashes of light  blurred or distorted vision  blind spots Some people "often describe their vision loss as a curtain coming down over the eye." If left untreated, CMV retinitis results in blindness. Therapies for CMV Standard treatment for CMV retinitis is iv (intravenous) ganciclovir or foscarnet. In some cases where CMV becomes resistant to these drugs doctors may use both of them in combination. These drugs have side effects and must be taken frequently. Recently the new anti-CMV drug cidofovir (Vistide(R), HPMPC) has been licensed in the US and is available in Canada through the EDRP (emergency drug release program). Previous reports on cidofovir have appeared in TreatmentUpdate 60. Into the eye Another approach is to place anti-CMV drugs directly into the eye. One research team has developed a slow-release form of ganciclovir, commonly called the "implant", that is inserted into the eye. They have found that the implant provides about 6 months of protection for CMV and costs about $5,000. One Canadian team has found that weekly injections of ganciclovir into the eyes of people with CMV retinitis useful. Now a group of American doctors report that injections of cidofovir need only be injected every six weeks. REFERENCES: 1. Jabs DA. Acquired Immunodeficiency Syndrome and the eye -- 1996. Archives of Ophthalmology 1996;114:863-865. 2. Hodge WG, Lalond RG, Samplis J and Deschenes J. Once-weekly intra-ocular injections of ganciclovir for maintenance therapy of cytomegalovirus retinitis: clinical and ocular outcome. Journal of Infectious Diseases 1996;174:393-396. 3. Ward-Able C, Phillips P and Tsoukas CM. The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS. Canadian Medical Association Journal 1996;154(3):363-368. H. Cidofovir in the eye --- once every 6 weeks. Study details Doctors in San Diego recruited 35 volunteers (subjects) with AIDS who also had CMV-retinitis. These subjects "did not benefit from or could not tolerate or refused iv (intravenous) ganciclovir or foscarnet." The study lasted for about 1.5 years and subjects remained in the study until:  death 31% (of subjects)  the study ended 17%  they developed CMV infection in another part of the body 14%  they developed another serious illness 9%  they had a detached retina 3%  they developed complications from the eye injections 9%  they refused to visit the study doctors as scheduled 3%. There were 34 males and 1 female in the study. Doctors divided the subjects into groups, A and B. In group A, "twenty-four eyes in 18 subjects" received injections of cidofovir. This was the first time they had received anti-CMV drugs. The twenty-nine eyes of the 17 remaining subjects had been previously treated with "ganciclovir, foscarnet or both." Eye injections -- the details Before the subjects received cidofovir they took probenecid 2 g orally and eight hours after the injections, 1 g to reduce the toxicity of cidofovir. They had their eye(s) and eye-lid(s) disinfected with Betadine(R) surgical scrub and then a mild anesthetic was sprayed. The eye(s) was then injected with a stronger anesthetic (Lidocaine 2%). Another injection containing cidofovir 20 µg followed. To lower the risk of bacterial infections in the eye, subjects used Polysporin ointment and to the reduce swelling and redness doctors gave them prednisolone eye drops. They received further injections of cidofovir every 6 weeks. On average subjects received 5 injections. Results Group A: "None of the eyes in group A had [retinitis which grew worse] during the study." Group B: "Four eyes (from two subjects) had [retinitis which grew worse]" during the study. These eyes belonged to two subjects who had retinitis which did not improve when previously treated with iv "ganciclovir or foscarnet." Eventually the damage to the retina in these two subjects healed. Complications -- major No intervention such as putting pellets of slow-release ganciclovir or, injecting eyes with cidofovir is 100% risk-free. Five eyes had reduced vision due to complications:  two eyes had reduced pressure inside the eyeball and this permanently reduced their vision to "counting fingers."  one eye could only detect "hand motions...despite rapid healing of the retinitis."  One eye underwent a reduction of vision due to a temporary drop in pressure inside the eyeball. "This [person also] became ill and [was] unable to return "[to the study clinic]." Complications -- minor Parts of the eye became swollen because of the injections but this problem cleared when the subjects used eye-drops containing prednisolone 1% and other drugs designed to reduce swelling. Survival Two thirds of subjects in group A died at the end of the study. Half of these subjects lived for 33 weeks. About 60% of subjects in group B died by the end of the study, half of whom lived for 47 weeks but the difference between the groups was not statistically significant. REFERENCES: 1. Rahhal FM, Arevalo F, Mungia D, et al . Intravitreal cidofovir for the maintenance treatment of cytomegalovirus retinitis. Ophthalmology 1996;103:1078-1083. III TESTING A. Absorbing more itraconazole by taking it with food Background Absorption of food and certain drugs is reduced in some PHAs because of intestinal damage caused by HIV or other microbes. As well, some PHAs don't produce enough acid in their stomachs to properly digest food. Lower-than-normal levels of stomach acid affects absorption of the antifungal drug itraconazole (Sporanox(R)). Doctors in Ann Arbor, Michigan, recruited 20 HIV-infected subjects for their experiment to find out how itraconazole absorption could be increased. Some subjects took itraconazole 200 mg:  on an empty stomach  with food  on an empty stomach with a supplement of acid (glutamic acid)  with food and an acid supplement Results Subjects who took itraconazole with food absorbed significantly more of the drug than other subjects. Use of the acid supplement did not increase absorption of itraconazole whether the drug was taken with or without food. REFERENCES: 1. Welage L and Kauffman C. The effect of food and gastric pH on the oral bioavailability of itraconazole in HIV+ patients. Abstract A031. B. Patients in hospitals may not get their medicine Study Details Another American team in Chicago conducted a study on 18 PHAs in the AIDS ward of a hospital to find out if they received their medicine as prescribed by the hospital's doctors. The doctors found, on average, that in 20% of cases:  some patients received too little medicine  others received too much In cases where intravenous antibiotics, antifungals and antivirals were prescribed, an average of 26% of patients did not receive the dose prescribed by their doctors. REFERENCES: 1. Max BE, Itokazu G, Danziger LH, et al . Do hospitalized patients receive their prescribed medications? Abstract N010. C. Saquinavir levels reduced by rifabutin Study details Doctors in Ottawa enrolled 12 HIV-infected men to test the effect of rifabutin 300 mg/day on the amount of saquinavir that is absorbed and ends up in the blood. They found that rifabutin reduces levels of saquinavir in the blood by 40%. So doctors treating PHAs taking this combination are going to have to increase their dose of saquinavir, perhaps by 40%. REFERENCES: 1. Sahai J, Stewart F, Swick L, et al . Rifabutin reduces saquinavir plasma levels in HIV-infected patients. Abstract A027. D. Survival decreases under managed care Background Over the past 5 years doctors in the US have found that increasing numbers of their patients have their medical bills paid for by agencies called HMOs (health maintenance organizations). Today HMOs are large, covering tens of thousands of patients, are increasingly influential, and can force doctors to reduce their fees. This in turn cuts the costs to the HMOs and lowers the income of doctors. Some doctors complain about HMOs which don't allow them to order certain expensive tests, carry out costly procedures or prescribe high-priced drugs, even if these options are in the best interests of their patients. This system of health care run by HMOs is called managed care. One team of doctors has been monitoring 1,000 men with HIV/AIDS to find out the effect managed care has on their health. Results The doctors found that 50% of men who had AIDS at the time they entered the study or who developed AIDS while in the study lived for 17 months under managed care. The equivalent figure for men who were in the traditional fee for service system (which exists in Canada) was 30 months. This difference--an increase in survival time of 60% -- was [statistically] significant, that is; not likely caused by chance alone. REFERENCES: 1. Palenick J, Graham NMH, Wu A, et al . Poorer survival among AIDS patients enrolled in managed care organisations versus traditional indemnity insurance. Abstract N024. Copyright (c) 1996 - CATIE. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. Direct Dial: v.34+: 714.248.2836; v.120/ISDN: 714.248.0433 Internet: telnet:aegis.com www: http://www.aegis.com