TreatmentUpdate45 - Volume 4, No. 5 - 1993 Community AIDS Treatment Information Exchange 517 College Street, Suite 324, Toronto, Ontario M6G 4A2 416.944.1916 or 800.263.1638 Table of Contents ----------------- I HIV/AIDS Theory A. T-cells in the blood and lymph nodes II ANTI-HIV AGENTS A. Searching for an effective therapy B. Passive immunotherapy--the New York experience III IMMUNOMODULATORS A. Isoprinosine for PCP and toxo? B. A clinical trial of beta-carotene IV INFECTION FIGHTERS A. Diarrhea B. A pilot study of colostrum C. Mepron versus Septra D. PCP prevention - aerosol pentamidine verus dapsone and pyrimethamine E. Clinadamycin and primaquine for PCP --------------- I HIV/AIDS THEORY A. T-cells in the blood & lymph nodes * BACKGROUND Researchers at the NIH (National Institutes of Health, Bethesda, Maryland) have found that most HIV in an infected person is not in T-cells in the blood. It turns out that most of the virus is in the lymph nodes/tissues throughout the body. Some readers will not be surprised; only 2% of the T and B cells (lymphocytes) are normally found in the blood. * SIV SIV (simian immunodeficiency virus) is "related" to HIV and can cause the equivalent of AIDS in some monkeys. Researchers at military bio-medical centres and elsewhere in the USA and have been studying the effect SIV has on the immune system of monkeys. In experiments on 21 monkeys infected with SIV, the researchers monitored the CD4+ cell counts and health of the animals as the infection progressed. When first infected with SIV, the number of CD4+ cells in the blood fell and then rose rapidly as the animals recovered from this initial infection. A similar reaction has been noted in HIV-infected humans. What is interesting about the SIV research is: - blood levels of CD4+ cells did not match those in the lymph nodes - CD4/CD8 ratios and CD4+ cell counts "remained within the normal range in the lymph nodes throughout [the monkeys' lives]" while they declined in the blood - serious loss of an CD4+ cells does not happen until the lymph nodes are almost completely "immunologically" destroyed, even though blood levels of these cells may be less than in the lymph nodes. These findings complement those reported by workers at the NIH and elsewhere on HIV's interaction with the human immune system (reviewed in TreatmentUpdate 43). If only 2% of the body's T-cells are in the blood and the levels of T-cells in the blood are different from those in the lymph nodes, it seems that blood cells alone cannot provide a complete "picture" of what damage most of the virus (in the lymph nodes) is doing. This research raises questions about relying on analyses of T-cells in the blood to find out what HIV is doing in the lymph nodes/tissues. REFERENCES: 1. Pantaleo G. Graziosi C and Fauci AS. Mechanism of disease: The immunopathogenesis of human immunodeficiency virus infection. New England Journal of Medicine 1993;328(5):327. 2. Rosenberg YJ, Zack PM, White BD, et al. Decline in CD4+ lymphocyte population in the blood of SIV macaques is not reflected in the lymph nodes. AIDS Research and Human Retroviruses 1993;9(7):639-646. 3. Westermann J and Pabst R. Distribution of lymphocyte subsets and natural killer cells in the human body. Clinical Investigator 1992;70:539-544. 4. Cohen J. T cell shift: key to AIDS therapy? Science 1993;262: 175-176. II ANTI-HIV AGENTS A. Searching for an effective therapy * NCI QUESTIONS CURRENT RESEARCH Although many chemicals have been tested for their anti-HIV activity, only a few of them have been developed as treatments. These drugs (called nucleoside analogues) such as AZT, ddC, ddI, 3TC and D4T are still being tested in experiments on people with HIV infection. Although AZT may, in the short term, increase survival (compared to others who do not use AZT) in the long term this advantage is lost. Indeed, in a recent article in the journal Immunology Today the director of the NCI (National Cancer Institute, Bethesda, Maryland), Dr. Sam Broder and others state that the "immunologic improvement attained is only partial and [temporary]". Their article is important because it points out errors in current research on treatments. As well it highlights barriers to an effective therapy. * PROBLEMS WITH CURRENT THERAPIES According to the NCI scientists, the "partial and [temporary]" benefit from current therapies is due to: - weak drugs; AZT and related drugs can only "partially [suppress]" production of HIV - viral resistance; HIV may develop resistance to existing drugs. The NCI researchers carefully noted that the link between viral resistance and declining CD4+ cell counts "has not yet been formally proven." - toxicity to the immune system; AZT and related drugs can impair the efficiency and effectiveness of the immune response * HURDLES TO OVERCOME The researchers stated that even if an effective anti-HIV therapy is found, it may not be able to provide "complete and prolonged [rebuilding of the immune system]." Even if HIV replication could be stopped completely, there are still events taking place that will not be immediately affected. These include: - T cell suicide (apoptosis; programmed cell death) - autoimmune activity; the immune system attacking itself - the release of chemical signals that reduce the effectiveness of the immune system - a key part of the immune system's early warning defenses, APCs (antigen presenting cells), become damaged and dysfunctional. This makes it difficult to contain infections - additional damage to the immune system caused by herpes viruses such as CMV as well as by the bacteria that cause TB. * THE LYMPH NODES/TISSUES Finally, there is the research on lymph nodes. The immune system's cells in the lymph nodes/tissues are very important. These cells act as filters and "trap" invading microorganisms. Researchers think that for the first 10 to 15 years after HIV infection the immune system can keep most of the virus within the lymph nodes/tissues. Eventually, however, the nodes become severely damaged and break down. For anti-HIV agents to be effective they must be able to block production of virus in the lymph nodes. While these barriers may make treating people with HIV/AIDS difficult, they can at least help people steer clear of therapies that (1) ultimately do not increase survival or improve quality of life and (2) may also be toxic to the immune system. As well, these barriers act as a minimum standard that potential anti-viral therapies must meet if they are to be effective. REFERENCES: 1. Yarchoan R. Mitsuya H. and Broder S. Challenges in the therapy of HIV infection. Immunology Today 1993;14(6):303309. 2. Pantaleo G. Graziosi C and Fauci AS. Mechanism of disease: The immunopathogenesis of human immunodeficiency virus infection. New England Journal of Medicine 1993;328(5):327. 3. Rosenberg YJ, Zack PM, White BD, et al. Decline in CD4+ lymphocyte population in the blood of SIV macaques is not reflected in the lymph nodes. AIDS Research and Human Retroviruses 1993;9(7): 639-646. B. Passive immunotherapy: the New York experience * BACKGROUND Some researchers think that one reason symptom-free people with HIV infection eventually develop symptoms is they no longer produce supposedly "protective" antibodies that attack HIV. Based on this theory infusions of protective antibodies (called passive immunotherapy) to people with symptoms of HIV infection should improve their condition. Results from several uncontrolled studies suggest that antibody infusions can help relieve some symptoms in people with AIDS. We now report on results from a double-blind, placebo-controlled trial in New York. * ANTIBODIES AND STUDY DETAILS Blood was collected from symptom-free HIV-infected subjects who had more than 400 CD4+ cells. Blood from donors not infected with HIV was also used in this study as a control, for comparison. Subjects were divided into 2 groups or 'arms'. Thirty-one subjects were randomly assigned to receive 250 ml of plasma containing anti-HIV antibodies every 4 weeks. Another 32 subjects were also randomly assigned to receive 250 ml of plasma without anti-HIV antibodies every 4 weeks. All subjects had AIDS and the average CD4+ count was about 39 cells. At least half of the subjects were monitored for 65 weeks. * DROPOUTS Thirty-six subjects left the study at various points in time; 17 in the arm given anti-HIV antibodies and 19 in the arm given ordinary plasma. Reasons for leaving included reasons such as "too weak to travel [to the study site]" by 13 subjects; a desire to take drugs/ therapies forbidden by the protocol, 9 subjects. No subject left because of toxic effects from the plasma. * RESULTS-CD4+ AND CD8+ CELLS The study doctors found that the CD4+ cell count "steadily declined in both [arms of the trial] once they entered the study. According to the study doctors, "there were no significant changes in the CD8+ [cell] count...during the study period." There was no difference between the two arms of the trial in the rate of CD4+ cell count decline. * RESULTS-VIRAL PRODUCTION There appeared to be no significant decline in (1) blood levels of HIV or (2) the ability to grow Virus from samples of blood cells from either arm of the study. An indirect and imprecise measure of viral production is measurement of the HIV protein p24. Ten of 12 subjects with high levels of p24 before the study had a reduction of about 50% in their p24 levels "during the first 6 months of [receiving plasma with anti-HIV antibodies]." Four of 9 subjects in the control arm (who received ordinary plasma) also had the same decrease. * RESULTS BETA2-MICROGLOBULIN (á2-M) Produced by the immune system, blood levels of á2-m rise as the effectiveness and efficiency of the immune response declines. There were no significant changes in blood levels of á2-m between or within both arms of the study. * RESULTS_INFECTIONS Eighteen subjects receiving anti-HIV antibodies and 16 subjects in the control arm developed new life-threatening infections. According to the study doctors "the types of [life-threatening] infections were similar in both groups." * SURVIVAL Nearly 80% of subjects died while in the study, deaths were the same in either arm. About half of the group receiving anti-HIV antibodies lived for 88 weeks, the equivalent figure for the other arm was 59 weeks. This difference was not statistically significant. Other calculations using the following did not produce statistically significant results: CD4+ cell count at the start of the study, detectable p24 antigen, dose of AZT, or the time to the first life-threatening infection. Infusions of anti-HIV antibodies did not reduce production of HIV, B2-microglobulin or raise CD4+ or CD8+ cell counts. * TOXICITY Some subjects had allergic reactions to the infusion of plasma. Treatment with antihistamines was sufficient to relieve symptoms. * SUMMARY Although there initially appeared to be trends in improved survival, and "delayed occurrence of [life-threatening] infections" among subjects given antibodies from HIV-infected donors, these trends did not become statistically significant. Eventually the survival curves of the two arms of the study converged. This meant that survival in both arms was the same. As well, there was no "significant effect of passive [immunotherapy] on [production of HIV]". Passive immunotherapy had no beneficial effect on other laboratory measures such as á2-microglobulin, CD4+ or CD8+cell counts. * PREVIOUS STUDIES Although previous trials found passive immunotherapy beneficial, these studies were "shorter, smaller, uncontrolled investigations", according to the New York investigators. Another randomized trial in Paris (see TreatmentUpdate 31 for details) was not "blinded". In that study both doctors and subjects knew what product they received. * A MORE SOPHISTICATED MODEL? Apparently the New York doctors did not consider that their whole approach may have been wrong. Recent research suggests that the ability of the immune system to contain HIV infection may depend on its response to this infection. A response that is T cell-based, that favours CMI (cell mediated immunity) may be more protective than a response based largely on B cells and antibodies (humoral immunity). If this theory is correct then infusions of anti-HIV antibodies alone should not have a significant impact. For background information on CMI and helping the immune system withstand HIV infection please see TreatmentUpdate 43. REFERENCES: 1. Jacobson JM, Colman N. Ostrow NA, et al. Passive Immunotherapy in the treatment of advanced human immunodeficiency virus infection. Journal of Infectious Diseases 1993;168:2998-305. 2. Yarchoan R. Mitsuya H. and Broder S. Challenges in the therapy of HIV infection. Immunology Today 1993;14(6):303309. 3. Shearer GM and Clerici M. T helper cell immune dysfunction in asymptomatic, HIV-1-seropositive individuals:the role of Th1/Th2 cross-regulation. Chemical Immunology 1992;54:21 43. 4. Clerici M, Shearer GM. A TH1/TH2 switch is a critical step in the etiology of HIV infection. Immunology Today 1993;14(3):107- 111. III IMMUNOMODULATORS A. Isoprinosine for PCP/toxo? * BACKGROUND Results from a large placebo-controlled trial in Scandinavia in the late 1980s suggested that the immune booster isoprinosine (inosine pranobex) could delay the appearance of life-threatening infections in HIV-infected subjects with less than 500 CD4+ cells. In that study, subjects given isoprinosine were less likely to develop the life-threatening pneumonia PCP compared to others given a dummy or placebo. At first researchers thought that isoprinosine might have had anti-HIV activity. More recent work suggests that it has no anti-HIV effects in laboratory experiments with cells and viruses. * THE B-VITAMIN PABA Researchers at the NIH (National Institutes of Health, Bethesda, Maryland) have found that part of isoprinosine resembles the B-vitamin called PABA (para amino benzoic acid). PABA is important not just for humans but also for microorganisms that cause PCP and the life-threatening brain infection toxo (toxoplasmosis). Sulpha drugs such as those used to treat PCP and toxo work in part, because they 'resemble' PABA. The microorganisms are 'tricked' into using the drugs rather than PABA and they are then not able to grow, and eventually die. The NIH researchers found that part of isoprinosine in lab experiments was able to block the growth of the microorganisms that caused PCP and toxo. * EXPERIMENTS ON RATS The researchers used isoprinosine both as a treatment and for prevention of PCP in rats but the drug was not effective. As the breakdown of isoprinosine in rats may be different from the way humans process the drug, the lack of benefit was not surprising. Indeed, within just over an hour of giving rats part of the isoprinosine molecule, blood levels had fallen by 50%. * FUTURE USE Since isoprinosine was not an effective anti-PCP agent by itself (like dapsone or pyrimethamine) the NIH scientists suggest that the drug may be more useful in combination with an antibiotic. The patent on isoprinosine will expire soon and this will reduce financial incentives for research on this compound. REFERENCES: 1. Kovacs JA, Powell F. Voeller D, and Allegra C. Inhibition of Pneumocystis carinii dihydropteroate synthease by paraacetamidobenzoic acid: Possible mechanism of action of isoprinosine on human immunodeficiency virus infection. Antimicrobial Agents and Chemotherapy 1993;37(6):1227-1231. B. A clinical trial of beta-carotene * TRIAL DETAILS Researchers at Oregon Health Sciences University have recently conducted a small clinical trial of Betacarotene (á-carotene) in subjects with HIV infection. The trial was designed as a double-blind, placebo- controlled study with two arms; one group or arm of the study would get á-carotene, the other group or arm would receive a dummy or placebo. Twenty-one subjects were enrolled, only one subject was female. The protocol called for half the group to receive 180 mg/day of á-carotene for 4 weeks and then be given placebo. The other half would receive a placebo for the first 4 weeks and then be switched over to B-carotene. Subjects in this trial had wide range of CD4+ cell counts from under 100 cells to over 600 cells. Sixteen subjects used AZT, ddI and/or ddC. * SIDE EFFECTS Apart from a "slight orange skin colour" no subjects reported any side effects. Lab tests did not detect any blood/bone marrow, liver or kidney toxicity. * RESULTS CD4+ CELLS á-carotene caused statistically significant increases in the total white blood cell count, the %CD4 cells and the CD4/CD8 ratio compared to others who received placebo. That is, these changes were not likely due to chance alone. The number of antibody-producing B cells also increased. In subjects on placebo the numbers of all the cells measured fells * á-CAROTENE ... The researchers do not know why supplements of á-carotene helped increased blood levels of the various cells. It may have been that á-carotene helped to protect cells from damaging chemicals called free radicals. * ... OR VITAMIN A? Alternatively, á-carotene is converted into vitamin A by the body. This conversion is carefully controlled and is done only when needed. Vitamin A is important for maintaining the immune system. Bad eating habits, diarrhea, infections, fever and loss of appetite may cause deficiencies of various nutrients and increase the body's need for vitamin A. Thus, á-carotene may have had several effects which all played a role in increasing the blood counts seen in this study. * UNANSWERED Questions There were a number of problems with this study. Although 21 subjects enrolled, 4 dropped out. Data analysis was then restricted to a total of 17 subjects; 13 subjects who completed both phases of the study, 3 who completed the initial 4 weeks on á-carotene and 1 subject who completed the first 4 weeks on placebo. Clearly, a larger and longer study is needed to confirm the results from this promising pilot study and also to find out how long the benefits of B-carotene might last. Studies of continuous use of Bcarotene in non-HIV-infected people have found that the immune-boosting effects begin to decline after 2 months. Thus, it is possible that the same effect may be seen in HIV-infected subjects. If this does happen, perhaps intermittent dosing-two months on, one month off-may be needed. Please read TreatmentUpdate 39 for more details. REFERENCES: 1. Coodley GO, Nelson HD, Loveless MO and FoLk C . B-cas otene in HIV infection. Journal of Acquired Immunodef ciency Syndromes 1993;6:272-278. 2. Prabhaia RH, Garewal SH, Hicks MJ, et aL The effects of 13cis- etinoic acid and B-carotene on cellular immunity in humans. Cancer 19ø.1;67:1556-1560. 3. Fryberg DA, Mark R. Askenase PW and Patterson TF. The inmunostimulatory effect and safety of á-carotene in patients witn AIDS, in: AIDS International Conference on AIDS, Amsterdam, the Netherland's, July 19-24, 1992. Amsterdam:Congrex Holland, 1992;PoB 3458 (abstract). IV INFECTION FIGHTERS A. Diarrhea * BACKGROUMD Diarrhea is a common problem in people with HIV/ AIDS. In as many as 30% of cases doctors cannot find the cause of diarrhea. In such cases a number of drugs can be used to reduce the severity of symptoms. Narcotics such as codeine, morphine, opium (Lomotil(R) Immodium(R)) can sometimes help. Bulking agents with fibre such as Metamucil(R) can be used to fill the intestine and provide some relief. Large doses of á-carotene (equivalent to 150,000 IU of vitamin A activity or more) may help in mild cases of diarrhea. * 'Crypto' A large number of microorganisms can cause diarrhea. Perhaps the most worrying is C. parvum (Cryoptosporidium parvum) for this report shortened to 'Crypto'). This parasite can case life-threatening diarrhea. Over 90 drugs have been used to try to treat this infection but none have been consistently effective. One product being tested for its' anti-diarrhea effect is colostrum. * COLOSTRUM This product is made by cows after they have given birth. It has a large concentration of antibodies that protect the calf from infection until its own immune system has become fully functional. The antibodies in colostrum can attack bacteria, parasites and viruses. When "newbom" calves are not given colostrum they die. Doctors in Germany have recently finished a pilot study using colostrum on humans with AIDS and other immunodeficiencies. In the next section we report their results. B. Pilot study of colostrum * STUDY DETAILS German researchers enrolled 27 HIV-infected adults, and 2 children with the same infection along with several other subjects with immunodeficiencies. There were six females and 31 males. All subjects had diarrhea for a minimum of 2 weeks and at least 4 times/day. Thirteen of the 29 HIV-infected subjects were also taking AZT, Bactrim/Septra, injections of antibodies (gamma globulin), fluconazole, ethambutol and rifabutin among other agents. In the past drugs such as Flagyl, Cipro, Bactrim/Septra and spiramycin were used without success against diarrhea. * COLOSTRUM "Colostrum was taken from cows within the first 10 hours after giving birth." All animals were healthy and were being observed by veterinarians. The colostrum had fats removed and was reduced to a concentrated form. Subjects received "100 ml of a 10% solution of colostrum for 10 days" 30 minutes before breakfast. Subjects received a second course of colostrum if diarrhea occurred after the first course of the drug. We will report results on the HIV-infected subjects. * RESULTS-RESPONDERS Twenty-one of the 29 HIV-infected subjects improved when given the colostrum preparation. In subjects who improved, their average number of bowel movements fell from 7 per day to 3 per day. After the first course of the study colostrum was not given again for 10 days. At the end of this period the average number of bowel movements increased to about 5 per day. Those 21 subjects who responded to the therapy stopped losing weight. * RESULTS-NON-RESPONDERS The researchers investigated the 8 HIV-infected subjects who did not respond. Two subjects had Kaposi's sarcoma in their intestines so the doctors were not surprised that colostrum was not helpful. Another subject needed longer courses of colostrum-8 weeks before diarrhea cleared. Another subject had "ten to fifteen bowel movements per day" but technicians could not detect Crypto in his stool samples. Two other subjects had more than 10 bowel movements per day and the doctors could not find any cause for this problem. * RELAPSE "Diarrhea recurred...within 4 weeks after the first four weeks of the study in about 1/3 of subjects." Most subjects improved when treated once again with colostrum. * SIDE EFFECTS Nausea (3 subjects) and gas (4 subjects) were the side effects reported. No life-threatening side effects happened during the study. * PARASITES In 1/3 of the subjects a microorganism that could have caused the diarrhea was detected. They included, Gardia lamblia, Blastomyces hominis, spiral bacteria, Campylobacter jejuni and Cryptosporidia species. * SUMMARY In this pilot study 21 of 29 subjects with HIV/AIDS and severe diarrhea improved when given 1 or more courses of colostrum. Diarrhea recurred when the doctors did not give further colostrum to the subjects. This may mean that patients with AIDS-related diarrhea may have to use colostrum on a regular basis. In another study, doubling the dose of colostrum (10 g twice daily) did not cause any life-threatening side effects. Many subjects complained about colostrum's "unattractive taste." The colostrum preparation used in this study is sold under the brand name LactobinX or LIG by Biotest, Dreieich, Germany. Placebo-controlled trials have started in Germany using Lactobin for AIDS-related diarrhea. The Immucell Corporation (Portland, Maryland) plans to test an oral colostrum extract called BACI (Bovine anticryptosporidium immunoglobulin). REFERENCES: 1. Rump JA, Axndt R. Arnold A, et al. Treatment of diarrhea in human immunodeficiency virus-infected patients with immunoglobulins from bovine colostrum. Clinical Investigator 1992;70:588-594. 2. Plettenberg A, Stoehr A, Stellbrink H-J, et al. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clinical Investigator 1993;71:4245. C. Mepron versus Septra * BACKGROUND One drug that has been recently licensed to treat the life-threatening pneumonia PCP is called Mepron(R) (atovaquone, 566C80). A recent trial compared the standard anti-PCP treatment Septra(R) against Mepron. Septra and Bactrim(R) are brand names of a combination of two antibiotics, trimethoprim and sulfamethoxazole. The Septra brand was used in this study. Although Mepron is weaker than standard therapy it has fewer side effects and can be used by people allergic to Bactrim/Septra. Doctors have also used Mepron to successfully treat the life-threatening brain infection toxo (toxoplasmosis). We now present a detailed report on a trial using Mepron for PCP. * SUBJECTS All 322 subjects in this study had "AIDS, untreated PCP, fever, symptoms of [a lung infection] or chest xray pictures which looked as if the subject had pneumonia." As well, 96% of subjects were male and nearly 80% were using drugs to prevent the development of PCP. About 70% of the subjects had PCP before this study. * TRIAL DETAILS Subjects were randomly assigned to one of two groups or 'arms' of the study either to receive Septra or Mepron. Subjects assigned to the Septra arm received 2 double strength (DS) tablets of the drug/day. The others received 750 mg of Mepron three times daily. All drugs were given for 21 days. * EFFECTIVENESS Although 322 subjects entered the trial, 38 did not respond to the drugs used. At 21 days after entering the study 25 subjects or 18% of those given Mepron did not improve. The equivalent figure for the Septra arm was 9 subjects or 6%. Subjects were monitored after the 21-day course of antibiotics for up to 49 days. At that time 20% of subjects given Mepron and 7% of those given Septra did not respond to these drugs. This difference between the two arms of the study was statistically significant, that is, not likely due to chance alone. * SIDE EFFECTS More subjects given Septra had side effects compared to others who received Mepron. Side effects seen in the Septra arm included: - nausea - vomiting - constipation - dizziness - fever - rash More subjects given Mepron had diarrhea than others given Septra. This difference was statistically significant. * SURVIVAL Survival was clearly better in the Septra arm of the study. Eleven subjects assigned to receive Mepron died as did 1 subject given Septra. This difference between the 2 arms of the study was statistically significant. The subject in the Septra arm died of the "wasting syndrome." Four of the deaths in the Mepron arm were due to PCP and six others from various bacterial infections. * SUMMARY For the treatment of PCP Septra was "more effective" than Mepron. Subjects given Septra were more likely to: - recover from PCP - have more side effects (nausea, vomiting and constipation; 20% of subjects given Septra had side effects so severe that they had to switch therapies) - survive; this benefit may be due to Septra's broad antibiotic effects. The study doctors concluded that Mepron is a "useful altemative" "to [Bactrim/Septra] for patients with PCP who do not tolerate or do not respond to therapy with [Bactrim/Septra]." A liquid form Mepron is being tested. If enough of the drug is absorbed, patients may only need to take Mepron once a day. REFERENCES: 1. Hughes W. Leoung G. Kramer F. et al. Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis Carinii pneumonia in patients with AIDS. New England Journal of Medicine 1993;328:1521-1527. D. PCP preventlon: aerosol pentamidine versus dapsone-pyrimethamine * BACKGROUND Although Bactrim/Septra is the best drug to prevent PCP many patients cannot tolerate these antibiotics because of allergies to sulpha. Other options include aerosol pentamidine and the combination dapsone pyrimetharnine. A recent trial in Paris compared the use of aerosol pentamidine against the combination of dapsone-pyrimethamine as prevention from the life-threatening pneumonia, PCP, and the deadly brain infection, toxo (toxoplasmosis). * SUBJECTS All subjects had AIDS (CD4+ cell counts were less than 200 cells). No subject had PCP or toxo in the past. The researchers used data from 349 subjects; 176 in the aerosol pentamidine group and 173 in the daDsone-Derimethamine (DP) arm for the data analysis. Over 80% of subjects were male and had been using AZT for about 4 months when they entered the study. At least half of the subjects were monitored for about 1.5 years. The average CD4+ cell count was approxirnately 114 cells. * DRUGS Subjects assigned to the aerosol pentamidine arm (AP) received 300 mg once per month. Subjects received AP via a Respirgard II nebulizer. In the other arm, subjects received dapsone 50 mg/day along with pyrimetharnine 50 mg once weekly. To reduce the toxicity of those drugs to the bone marrow subjects received 25 mg/week of the B-vitamin folic acid. * RESULTS - PCP; 10 subjects in each arm of the study developed PCP. - toxo; a total of 51 subjects developed toxo; 18%in the AP arm and 11% in the DP arm. Clearly, subjects in the AP arm were at higher risk of toxo. This difference between the two groups was statistically significant; that is, not likely due to chance alone. - Survival-eighty-six subjects died; 41 in the AP arm and 45 in the DP arm. This difference was not statistically significant. Nine subjects died from PCP or toxo, 72 others from another "AIDS-related disease" and 5 died of other causes. * SIDE EFFECTS These were more common in the DP arm of the study. No subject died from any of the drugs used in the trial. * SUMMARY In this French study, subjects with AIDS were given 2 preventative regimens against PCP and toxo. One group received aerosol pentamidine 300 mg/month and the other dapsone 50 mg/day with 50 mg/week pyrimetharnine. As well, subjects given dapsone received 25 mg/week of the B-vitamin folic acid to protect their bone marrow from the toxic effects of dapsone/pyrimethamine. Equal numbers of subjects in both arms of the trial developed PCP. More subjects receiving aerosol pentamidine got toxo than did others who received dapsone-pyrimethamine. Survival was the same in both arms of the trial. REFERENCES: 1. Girard P-M, Landman R. Gaudebout E, et al. Dapsonepyrimethamine compared with aerosol pentamidine as primary prophylaxis against Pneuznocystis carinii pneumonia and toxoplasmosis in HIV infection. New England Journal of Medicine 1993;328:1514-1520. E. Clindamycin/primaquine for PCP * BACKGROUND For many people with HIV infection in North America a major cause of illness and death is the life-threatening pneumonia PCP. Although there are preventative drugs, they also have many side effects. The best drug for prevention of PCP is Bactrim(R)/Septra(R). Many patients are allergic to these drugs. Aerosol pentamidine can get to most of the lungs but does not protect the rest of the body from the parasite that causes PCP. In the late 1980s, doctors in Montreal tried a combination of the antibiotics clindamycin and primaquine as a novel treatment for PCP. Their success showed that it was possible to treat PCP with this combination. Since then doctors in the EC and USA have confirmed the Montreal results. The researchers in Montreal have recently completed a trial to compare the effectiveness of clindamycin/pyrimethamine againstthatof Bactrim/Septra. * TYPE OF SUBJECTS All subjects in this study were HIV-infected adults and this was their first attack of PCP. Most subjects were male and apart from PCP were not having any other serious complications. Subjects were randomly assigned to one of two arms of the study. Neither study investigators nor subjects were told which drugs they were receiving. The average CD4+ cell count was between 73 and 78 cells. The subjects were having symptoms of PCP for about 2 weeks before entering this study. Over 80% of them had not been using drugs to suppress PCP. * STUDY DETAILS BACTRIM/SEPTRA Bactrim/Septra are the brand names of a combination of two antibiotics; T (trimethoprim) and S (sulfamethoxazole). If subjects were assigned to the Bactrim/Septra arm they received the drugs intravenously for "10 days in [a] hospital and then orally for another 11 days either in or out of [a] hospital". Subjects who weighed more than 60 kg received "320 mg of [T] and 1600 mg [S] every six hours." Those who weighed less than 60 kg received "240 mg [T] and 1200 mg [S] every six hours." The doctors gave the subjects 5 mg/day of the B-vitamin folic acid to protect the bone marrow from the toxicity of Bactrim/Septra. A total of 31 subjects received Bactrim/Septra. * STUDY DETAILS--CLINDAMYCIN/PRIMAQUINE Subjects received the antibiotic clindamycin by infusion into a vein in a dose of "600 mg/6 hours for 10 days and then orally in a dose of 450 mg every 6 hours for 11 days for [subjects] who weighed [more than] 60 kg." For [subjects who weighed less than] 60 kg]" clindamycin in a dose of 450 mg/6 hours for the first 10 days and then 300 mg/6 hours for the next 11 days. All these subjects received 15 mg/day of primaquine. A total of 34 subjects received clindamycin/primaquine. Subjects in both arms of the study received 25 mg/6 hours of the antihistamine "diphenhydramine" (gravol) after the 5th day. In cases where a rash developed the dose was doubled. * RESULTS-EFFECTIVENESS Both drug regimens were equally effective against PCP. Survival and time free from PCP were the same in both groups. * RESULTS-TOXICITY BACTRIM/SEPTRA About 20% of subjects initially receiving Bactrim/ Septra could not tolerate this regimen and had to be switched to clindamycin/primaquine. According to the investigators, signs/symptoms of toxicity included: - low levels of white blood cells - increased blood levels of liver enzymes - altered mental status (with or without hallucinations) - nausea and vomiting - rash One subject developed heart dysfunction * RESULTS--TOXICITY CLINDAMYCIN/PRIMAQUINE In this arm of the study, 6 subjects had to stop taking the antibiotics because of severe rash (5 subjects) and [puritis] (1 subject). Rash and diarrhea were common side effects in this arm of the study. All in all, subjects experienced more side effects when given Bactrim/Septra than others given clindamycin/ primaquine. This difference was not statistically significant. * SUMMARY In this trial, either Bactrim/Septra or clindamycin/ primaquine were equally effective against PCP. Subjects experienced fewer side effects when given clindamycirdprimaquine than those given Bactrim/ Septra. This difference was not statistically significant. Subjects given Bactrim/Septra were more likely to have nausea and vomiting as well as low blood levels of sodium. For subjects given clindamycin/ primaquine "rash and diarrhea were more frequent and severe" comparedto others given Bactrim/Septra. Use of 5 mg/day of the B-vitamin folic acid did not reduce the toxicity of Bactrim/Septra. Survival averaged between 15 and 17 months and the time free from PCP (10 to 13 months) was not significantly different between the study arms. The study doctors suggest that Bactrim/Septra should remain the drug of choice for treating PCP in patients with AIDS. They also suggested that a larger trial of these anti-PCP agents be conducted. * REDUCING ALLERGES TO BACTRIM/SEPTRA One way to decrease the toxicity of this drug is a process called desensitization. Patients are given very small doses of Bactrim/Septra and tolerace is gradually built up. This will not help every person with HIV/AIDS, but some doctors have found it useful. One desensitization protocol appears in TreatmentUpdate 24 and another will appear in TreatmentUpdate 46. REFERENCES: 1. Toma E, Fournier S. Dumont M, Bolduc P and Deschamps H. Clindamycirl/primaquirle versus trimethoprim - sulfamethoxazole as primary therapy for Pneumocystis carinii pneumonia in AIDS: a randomized, double-blind pilot trial. Clinical Infectious Diseases 1993;17:178-184. Copyright (c) 1993 - Community AIDS Treatment Information Exchange. Noncommercial reproduction encourage.