TreatmentUpdate60 - Volume 7, No. 6 - June 1995 *********************************************** Community AIDS Treatment Information Exchange, 420 - 512 College St, Toronto, Ontario, Canada, M6G 4A2 *********************************************** I ANTI-HIV AGENTS A. 3TC (Lamivudine)--early results * BACKGROUND Developed in Montr‚al, 3TC is a chemical 'related' to AZT. Experiments on HIV-infected humans using this drug are underway in North America and in the European Union. In this article we report results from 2 studies looking at safety and anti-HIV effects, as well as the development of viruses resistant to 3TC. Detailed results from a study testing a combination of 3TC and AZT had not been released as we went to press. * STUDY DETAILS All 114 subjects were male and had less than 401 CD4+ cells. Researchers randomly assigned 15 subjects to one of 6 groups, each group taking a different dose of 3TC. After each dose, researchers looked for side effects of 3TC. When subjects did not experience toxicity, the researchers increased their dose of 3TC. Subjects took 3TC in "two equal doses every 12 hours". The doses of 3TC used were 1/2 or 1, 2, 4, 8, 12 or 20 mg/kg of body weight/day. Six months after entering the study, subjects taking lower doses were allowed to increase their dose to 8 mg/kg/day, which is about 300 mg/day. * TOXICITY The researchers claimed that "3TC was well tolerated" at all doses. Common side effects included: - diarrhea 69% of subjects - fatigue 56% - headache 49% - coughing 39% - problems sleeping 30% - muscle pain 25% - nausea/vomiting 19% The researchers stated that many of these symptoms were temporary and "mild". Less than 5% of subjects developed low blood levels of white blood cells and platelets. Others developed high blood levels of liver enzymes. According to the researchers, all these changes were temporary. * DEATHS, DISEASES AND DROPOUTS Fourteen subjects stopped taking 3TC mostly "because of [falling] CD4+ cell counts." Five of 11 subjects who developed life-threatening infections or cancers left the study. One subject left because of headaches and 2 subjects died. There were no significant differences between dose groups when researchers looked at who developed AIDS. * COUNTING CD4+ CELLS AND OTHER LAB TESTS Before potential subjects received 3TC, doctors made sure that at least 2 CD4+ cell counts were done. They found that statistically significant increases occurred even before subjects received 3TC. In half of the subjects the increase was about 17 cells. CD4+ cell counts reached their highest level during the first 2 months of the study. Half of the subjects had their CD4+ counts return to their pre-study level after receiving 3TC for 12 weeks. Despite using different ways of analyzing data, researchers could not find a link between the dose of 3TC and an increased CD4+ cell count. Researchers also measured production of virus, levels of beta2- microglobulin and neopterin, but again there were no statistically significant links between doses of 3TC and changes in those laboratory measurements. * HIV RESISTANCE AGAINST 3TC In other developments, researchers in the laboratory of virologist Mark Wainberg (Montr‚al) and elsewhere have been studying the long term effect of 3TC on HIV in 39 subjects with less than 301 CD4+ cells. Subjects received various doses of 3TC (as listed earlier). Technicians found HIV resistant to 3TC in blood samples from 13 subjects. Resistance developed in subjects taking low doses (1/2, 1 or 4 mg/kg/day) as well as in subjects taking high doses (8, 12 and 20 mg/ kg/day). Resistance appeared as early as 4 months in some subjects, while in others it appeared in the 10th month of using 3TC. The researchers could not find any link between the dose of 3TC used and the development of resistance. As well there was no connection between the development of HIV resistant to 3TC and declining CD4+ cell counts and the development of life-threatening infections. A number of studies of 3TC are underway. There is an 'open-label' trial where subjects can get 3TC taken orally. Subjects will be randomly assigned to receive either a low dose (150 mg/day) in two divided doses, or 300 mg day, again in a divided dose. Subjects taking the 150 mg dose may also take AZT. Physicians in Canada and the USA interested in enrolling their patients in the open label programme may call 1-800-248-9757 (personal communication, D. Donaldson, Glaxo-Wellcome and D. Maclean). REFERENCES: 1. van Leeuwen R, Katlama C, Kitchen V, et al. Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic Human Immunodeficiency Virus infection: a phase I/II study. Journal of Infectious Diseases 1995;171:1166-1171. 2. Wainberg MA, Solomon H, Gu Z, et al. Development of HIV-I resistance to (-)2'-deoxy-3'-thiacytidine in patients with AIDS and advanced AIDS-related complex. AIDS 1995;9(4):351-357. B. AZT and L-697,661 * BACKGROUND AZT and related drugs (ddC, ddI, 3TC, d4T--nucleoside analogues) are supposed to have anti-HIV activity by affecting a key viral enzyme RT (reverse transcriptase). There is also a different group of anti-HIV agents call non-nucleoside drugs that can affect RT, these drugs include nevirapine and L-697,661 (L-697). In laboratory experiments with cells and HIV, the virus becomes quickly resistant to drugs such as nevirapine and L-697. In experiments on HIV-infected humans, researchers confirmed similar results. We now report results from a study where researchers tested combinations of AZT and L-697. * STUDY DETAILS Researchers in Frankfurt enrolled 119 subjects (109 men, 10 women) for a study where some subjects received combinations of AZT and L-697. Subjects had CD4+ cell counts ranging between 200 and 500 CD4+ cells, with the average count at about 350 CD4+ cells. No subject used AZT before entering this study nor did any have AIDS. Researchers randomly assigned subjects to one of four groups or 'arms' of the study: - group 1: L-697 200 mg/8 hours - group 2: L-697 100 mg/8 hours and AZT 100 mg/day (low dose combination) - group 3: L-697 200 mg/8 hours and AZT 100 mg/8 hour (high dose combination) - group 4: AZT 100 mg/8 hours Each group had 30 subjects, except for the AZT only arm which had 29. Researchers conducted the study for about 1 year. During this time neither doctors nor their subjects were supposed to know which drug or combinations of drugs they received. The researchers could unblind the study after 6 months and subjects who remained in the study could receive the high dose combination (as in group 3) if they wished. * RESULTS-CD4+ CELLS Note: the researchers only released data on CD4+ cell counts for the first 6 months of the study. - L-697: compared to their pre-study values, subjects receiving L-697 alone had declining CD4+ cell counts. By the 6th month of the study, subjects in this group had lost at least 57 CD4+ cells. - Low dose combination: For the first 3 months, the average CD4+ cell count rose as high as 79 cells, after which it fell and was no longer statistically significant. - High dose combination: half the subjects had an increase of 55 CD4+ cells by the 3rd month of the study. After that point, the increase was no longer statistically significant. - AZT: these subjects had statistically significant increases in their CD4+ cell counts during the first 4 months of the study with half of the subjects maintaining an increase of 84 cells. By the 6th month of this study the increase was no longer statistically significant. * RESULTS-TOXICITY Subjects in this study experienced a number of side effects. The following differences in side effects among the groups were statistically significant: - nausea: subjects receiving AZT or combinations of AZT were 2 to 3 times more likely to have nausea than subjects receiving L-697 alone - irritability: 3 subjects taking AZT developed this problem while other subjects did not - 'sleeping problems': 4 subjects in the high dose combination group had this side effect while no other subjects did - rash: 6 subjects in the L-697 group and 3 others in the high dose group reported this side effect The researchers did note that six serious events occurred in the study, and in brackets we note in which arm of the study they enrolled: - 2 subjects committed suicide (1 each in the L-697 and AZT groups) - 1 'developed' lymphoma (AZT arm) - 1 developed an abscess near his rectum (low dose combination) - 1 had life-threatening inflammation of his appendix (low dose combination) - 1 subject developed Kaposi's sarcoma (group missing) * RESISTANCE TO L-697 Researchers tested blood samples taken during the study to check for HIV that had become resistant to L-697. At the start of the study, all HIV infected cells reduced virus production when treated with L-697. By the 2nd month, technicians found that HIV-infected cells had become resistant to L-697. Subjects who received combination therapy (AZT and L-697) had virus that did not become resistant until some time between the 4th and 8th month of the study. Blood samples from subjects receiving AZT alone always had virus that was affected by L-697. Researchers did not check for HIV resistant to AZT. * BEYOND RESISTANCE The researchers conducting this study performed sophisticated analyses of viral resistance and tried to understand this event. It appeared that subjects receiving L-697 alone had virus that was 100 times more resistant to the drug than when they entered the study. While that event is interesting, this study did not show that combination therapy reduced the risk of developing life-threatening infections/cancers that are the hallmark of AIDS. L-697,661 is made by Merck, West Point, Pennsylvania, USA. REFERENCES: 1. Staszewski S, Massari FE, Kober A, et al. Combination therapy with Zidovudine prevents selection of Human Immunodeficiency Virus type 1 variants expressing high-level resistance to L-697,661 a nonnucleoside reverse transcriptase inhibitor. Journal of Infectious Diseases 1995;171:1159-1165. II INFECTION FIGHTERS A. Who gets PCP despite prophylaxis? * BACKGROUND Although a number of drugs are available to treat and prevent the life-threatening pneumonia PCP, some HIV-infected patients still develop PCP. Researchers in the USA are beginning to investigate these cases of PCP despite use of preventative antibiotics (called PCP prophylaxis). * STUDY DETAILS Researchers used data from 473 men who had less than 200 CD4+ cells "within 6 months before they began [taking preventative doses of antibiotics] and 3 other men who had [less than 200 CD4+ cells] within 12 months before they began to use PCP prophylaxis." Thus researchers used data on a total of 476 men. Seventy-seven percent of subjects had never had an attack of PCP before entering this study; their use of preventative antibiotics is called primary prophylaxis. The remaining 23% of subjects had an episode of PCP before entering this study; their use of PCP prevention is called secondary prophylaxis. Drugs used to prevent PCP were Bactrim(R)/Septras (B/S), dapsone and/or aerosol pentamidine (A/P). * RESULTS-SWITCHING DRUGS The study began in 1989 with about 20% of subjects using B/S,73% using AP and 7% dapsone. According to the study doctors, "use of [B/S] doubled" during the study. This change happened to the same extent in subjects who had had or who had never had PCP before entering this study. * RESULTS-PCP Eventually 19% of subjects developed PCP. Doctors diagnosed PCP in one of two ways: - analyzing samples from the lungs 73% - improvement in subjects treated with anti-PCP drugs 27% Half of the subjects who had never had PCP before entering this study developed PCP within 12 months into this study. This group survived for about 2 years. Half of subjects who had had an episode of PCP before entering this study developed PCP roughly 8 months after entering this study. This group survived for about 1.2 years. This difference in survival between the 2 groups was statistically significant; that is, not likely due to chance alone. Changing the drug used for prevention did not appear to cause PCP. The type of PCP prophylaxis did not affect survival. Whichever drug subjects used when they first entered the study did not affect survival (in a statistically significant manner). Subjects having relatively high CD4+ cell counts (defined by researchers as 100 or more CD4+ cells) were more likely to stop using anti-PCP drugs than those with lower CD4+ cell counts. This event was statistically significant. * A DETAILED REVIEW Reviewing their data and making adjustments for changes over time, researchers found "that the most important independent factor for developing PCP [despite use of preventative drugs] was [a very low CD4+ cell count]." As well, the following factors appeared to provide protection from PCP: - use of B/S - cigarette smoking In their more sophisticated analysis, AZT was not linked to preventing PCP because, after "[CD4+] cell counts were considered, non-users [of AZT] had higher CD4+ cell counts than previous users who had lower cell counts." That cigarette smoking affected which subjects developed PCP is interesting. In earlier studies subjects who smoked cigarettes were more likely to develop PCP than those who didn't. The researchers warn that their results should not be used to encourage patients with HIV/AIDS to smoke as that causes lung problems. According to the researchers, the following proportion of subjects developed PCP at the cell counts listed: - 85%: who had less than 75 CD4+ cells - 75%: who had less than 50 CD4+ cells The study doctors decided that the microbe that causes PCP did not become resistant to any of the drugs used by subjects as prophylaxis. Indeed, subjects who used B/S as prophylaxis recovered from PCP when treated with the same drug. Finally the doctors stated that "more effective [regimens against the microbe that causes PCP need to be developed]." REFERENCES 1. Saah AJ, Hoover DR, Peng Y, et al. Predictors for failure of pneumocystis carinii pneumonia prophylaxis. Journal of the American Medical Association 1995;273(15):1197-1202. B. Experimental combinations for PCP and toxo * BACKGROUND Although drugs such as Bactrim/Septra and intravenous pentamidine are effective against the life-threatening lung infection PCP, they have side effects which some patients cannot tolerate. Researchers are testing a number of antibiotics by themselves or in combination to find alternatives to standard therapy. Scientists working for Glaxo-Wellcome have been testing several combinations of anti-PCP drugs in mice, and we report their results below. * MICE WITH PCP Researchers used mice with weakened immune systems who were infected with the microbe that causes PCP. They found that the drugs Mepron(R) (atovaquone, Wellvone(R)) and dapsone had anti-PCP activity when used by themselves. The following combinations had increased anti-PCP activity when used together rather than when used by themselves: - Mepron and azithromycin - Mepron and clarithromycin While the antibiotic rifabutin (Mycobutin(R)) had no anti-PCP activity by itself, in combination with Mepron, rifabutin had significantly increased anti-PCP effect. The researchers noted that none of the following drugs weakened the anti-PCP effect of Mepron- azithromycin, B/S, clarithromycin or dapsone. * Toxo In other developments, researchers in military biomedical centres and elsewhere in the USA have been testing various compounds for their anti-parasite activity. Results from their work suggest that extracts of the Chinese herb A. annua (quinghaosu) and another antimalarial drug, cycloquanil, can have anti-toxo effects in experiments with cells and parasites. That antimalarial drugs might be useful against the microbes that cause PCP/toxo is not surprising. The drug Mepron was being developed as an antimalarial until its anti-toxo/PCP effects were discovered. Fansidar is another antimalarial that some doctors prescribe to prevent toxo. In the next article we provide details about quinghaosu as an antimalarial drug and its use in the USA for treating PCP. REFERENCES: 1. Comley JCW and Sterling . Effect of atovaquone and atovaquone drug combinations on prophylaxis for Pneumocystis carinii pneumonia in SCID mice. Antimicrobial Agents and Chemotherapy 1995;39(4):806-81 1. 2. Holfels E, McAuley J, Mack D, et al. In vitro effects of artemisinin ether, cycloquanil hydrochloride (alone and in combination with sulfadiazine), quinine sulphate, mefloquine, pyrimethamine phosphate, trifluoperazine and verampil on Toxoplasmosis gondii. Anti- microbial Agents and Chemotherapy 1994;38(6):1392-1396. C. Certain drugs may weaken the anti-toxo effects of clarithromycin * BACKGROUND (For information on the symptoms and treatment of the life-threatening brain infection toxo, please read TreatmentUpdate 59.) One of the problems faced by doctors is that some patients with toxo may not be able to tolerate standard therapy--a combination of the antibiotic pyrimethamine and a sulpha drug (such as sulphadiazine). Doctors may sometimes substitute clindamycin in place of sulpha drugs. In the EU, some doctors have been experimenting with the antibiotic clarithromycin to prevent or treat toxo. As some of their patients at risk for toxo developed that infection despite use of clarithromycin, they began an investigation to try and understand what happened. * STUDY DETAILS Over a period of 20 months, doctors in France treated 21 subjects who had life-threatening MAC infection with a combination of antibiotics that included clarithromycin, which they took for 3 months. Thirteen subjects had anti-toxo antibodies in their blood, suggesting that they had been infected with the parasite that causes toxo (T. gondii). Before being treated for MAC, 1 subject had toxo but had completely recovered. During the 20 months, 4 subjects developed toxo after an average of 4 months of treatment with clarithromycin. None of the other 9 subjects with anti-toxo antibodies developed toxo. * RESULTS The researchers tried to find out why some subjects developed toxo. None of the following differences between the two groups of subjects was statistically significant: - CD4+ cell counts - length of time they had AIDS - chronic diarrhea - weight - use of other anti-toxo drugs The doctors did find that a difference in drug combinations between the 2 groups was statistically significant. Subjects who developed toxo were more likely to have been using Cipro, ethambutol, ddI and rifampin. * EXPLANATION As many people with HIV/AIDS can be using several drugs for different reasons, it is not surprising that these drugs might interact with each other. The researchers think that ddI might have reduced the absorption of clarithromyin while rifampin could have reduced blood levels of clarithromycin. The researchers note that they only had a small number of subjects in their study and that another study with more subjects should be conducted to investigate possible drug interactions. * WARNING The researchers warn that clarithromycin should not be given for prevention of toxo/MAC to patients who are also using rifampin. Patients using such a combination may also develop signs/symptoms of toxo. REFERENCES: 1. Raffi F, Struillou L, Ninin E, et al. Breakthrough cerebral toxoplasmosis in patients with AIDS who are being treated with clarithromycin. Clinical Infectious Diseases 1995;20:1075-1077. D. QHS (artemisinin)--experience with malaria * BACKGROUND Malaria kills between 1 and 2 million people each year. Although there are several antimalarial drugs available, the parasite that causes malaria is becoming increasingly resistant to them. In Asia, where malaria is a serious problem, researchers are continually trying to find and test new antimalarial compounds. * TARRAGON AND SAGEBRUSH In the past, practitioners of traditional Chinese medicine used the bark sweet wormwood (A. annua) to treat hemorrhoids and about 1700 years ago they documented its ability to "reduce fevers". More importantly, about 400 years ago, Chinese doctors documented its antimalarial activity. In the 1970s, Chinese researchers 'rediscovered' the antimalarial activity of A. annua and extracted the chemical QHS (quinghaosu or artemisinin). The weed A. annua is 'related' to plants such as sagebrush and tarragon. Plant scientists think that A. annua came from Asia. The weed can be found along the bank of the Potomac river in Washington, DC. The concentration of QHS in A. annua is low and researchers have only been able to extract about "2% of dry plant weight". A. annua growing in Sichuan province, China, is supposed to have the highest concentration of QHS. * QHS Pure QHS or artemisinin looks like "fine, colourless needles" and does not dissolve in water but can be mixed with oil forming a 'suspension'. Chinese researchers have made drugs 'related' to QHS and they are: - artemether - arteeher - artelinic acid * QHS AND MALARIA QHS and related compounds, used in China and Vietnam since the late 1970s, are potential treatments for malaria and up to 1 million humans with malaria have received QHS or its 'relatives'. Some researchers think that QHS causes the release of highly active molecules called 'free radicals', which damage the parasite that causes malaria. * EFFECTIVENESS AGAINST MALARIA Several forms of QHS have been tested and the total dose given over 3 to 5 days is: - tablets: 3g (50 mg/kg) or - injection (same dose) into muscle (QHS in oil or water). Most subjects with malaria recovered within 2 days. Relapse was more likely among subjects who received tablets than among those who received injections. In other studies, QHS-treated subjects recovered faster than others given chloroquine, quinine or mefloquine. In one study, 21% of subjects receiving QHS relapsed 1 month after treatment, while no relapse occurred among subjects given quinine during that time. QHS has also been made into suppositories and tested in at least 600 subjects. Giving adults 2800 mg over 3 days (50 mg/kg) produced "the best results". In trials comparing QHS or related compounds to standard therapy, preliminary results indicated that fewer subjects on QHS died. * TOXICITY In experiments with animals, QHS and related drugs "are considerably less toxic than [standard therapy]." Large doses of artemisinin compounds do cause side effects in 'large animals'. Symptoms of toxicity in dogs include "loss of spinal and pain responses, restlessness, tremors and incoordination...[problems breathing and standing], convulsions and [death]." According to one team of reviewers, there "have been remarkably few adverse effects in [humans]" caused by QHS or related drugs. In summarizing test results, they noted that "there has been no evidence of significant toxicity in over 4,000 [human] subjects entered into clinical studies." One research team warns that "for now, it is best to avoid use of [QHS] compounds in pregnant women with uncomplicated malaria...". * VERY RARE SIDE EFFECTS 1 of 82 subjects receiving artesunate and 3 of 39 [subjects] receiving artemether temporarily had a first-degree heart block". This seemed to have no further toxicity or cause any damage to subjects. Some subjects receiving more than 4 mg/kg of artemether had decreased red blood cell counts 4 days after receiving the drug. One week later they returned to normal. One subject who received "120 mg/kg" of artemesinin suppositories had temporarily increased blood levels of liver enzymes. In phase III studies in China, 6% of subjects using artemisinin suppositories had gastrointestinal problems such as nausea/vomiting, intestinal pain and diarrhea. As many as 25% of subjects using QHS and related compounds have temporary bouts of fever. * FUTURE USE The cost of developing QHS compounds to meet standards set by the US Food and Drug Administration (FDA) is high. As well, some researchers suggest that pharmaceutical companies do not make huge profits on "antimalarials and do not have an incentive to develop them". * AVAILABILITY In some Asian countries--China and Vietnam--QHS containing compounds are sold for the treatment of malaria in the form of tablets, suppositories or mixed with oil for injection. Some researchers think that longer courses of treatment--between 5 and 7 days--may provide better results than shorter courses. In our next article we report on the potential of QHS as a treatment for PCP/toxo. REFERENCES: 1. Klayman Dl. Quinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228:1049-1055. 2. Hien TT and White NJ. Quinghaosu. Lancet 1993;341:603- 608. 3. Wesche DL, DeCoster MA, Tortella FC and Brewer TG. Neurotoxicity of artemisinin analogues in vitro. Antimicrobial Agents and Chemotherapy 1994;38(8):1813-1819. E. QHS-Chinese herb for PCP? * STUDY DETAILS At an HIV/AIDS conference in San Francisco last summer, acupuncturist Susan Paul presented preliminary information on her use of QHS-related compounds in the treatment of "very early" PCP. Ms. Paul describes early PCP as "fatigue, lack of appetite and rapid [breathing] with a sense of chest constriction. At this stage there is no cough, and chest X-ray and sputum cultures will be negative." She has treated 13 subjects with PCP who could not tolerate standard anti-PCP therapy and who developed "very early" PCP. She prescribed the Seven Forests brand of Bellamoconda 15 (3 tablets, 3 times a day) and the Brion brand of QHS (2 grams, 3 times/daily) using loose, single granules. According to her regimen, "therapy is continued until the patient has been totally cleared of all symptoms for 7 to 10 days." * RESULTS She has not found any side effects with this therapy, noting that no patient experienced diarrhea. Ms Paul is currently monitoring 6 additional subjects who cannot tolerate standard anti-PCP prevention. These subjects have an average of 96 CD4+ cell counts and over a 3-month period have not developed PCP or toxo. Ms Paul notes that QHS also appears to prevent oral fungal infections. * LONG TERM OBSERVATION When questioned at the conference about long term results from her original group of 13 patients, Ms Paul said that 4 subjects no longer use the herb. One subject developed dementia and is dying; another developed the life-threatening brain infection 'crypto' (Cryptococcal meningitis); a third developed severe rectal warts, seizures and Kaposi's sarcoma. She has not been able to locate the 4th subject. One of her subjects took 20 times the normal dose and developed nerve damage. * QUALITY CONTROL We cannot verify the purity of the product used by Ms. Paul's subjects. Moreover, even doctors in Southeast Asia concede that factories manufacturing QHS may not produce a highly pure product. There are also some problems with her definition of PCP, as subjects could have been infected with other microbes. * PROBLEMS One possible problem with QHS is the way it is supposed to work. In treating patients with malaria, QHS causes the release of highly active molecules called free radicals. As patients with HIV/AIDS may have weakened defences against free radicals, chronic therapy with QHS may pose some risk. In experiments on mice with malaria, removing vitamin E (an antioxidant) from their diet increased the antimalarial activity of QHS. Trials with short courses or intermittent use of QHS may be one way to test this idea. According to Chinese research, QHS appears to boost CMI (cell-mediated immunity)--one part of the immune system that is weakened by HIV infection. This may be useful because many of the infections seen in AIDS can only be kept in check by CMI. Clearly, better studies need to be designed to test QHS' potential for some of the infections seen in AIDS. The quality of QHS used in Southeast Asia seems good enough for treating malaria, and perhaps researchers might consider this when making decisions about which form of the drug to use. REFERENCES: 1. Saah AJ, Hoover DR, Peng Y, et al. Predictors for failure of Pneumocystis carinii pneumonia prophylaxis. Journal of the American Medical Association 1995;273(15):1197-1202. 2. Holfels E, McAuley J, Mack D, et al. In vitro effects of artemisin ether, cycloguanil hydrochloride (alone and in combination with sulfadiazine), quinine sulfate, mefloquine, primaquine phosphate, trifluoperazine hydrochloride and, veridical on toxoplasmosis gondii. Antimicrobial Agents and Chemotherapy 1994;38(6): 1392-1396. 3. Paul S. Herbal prophylaxis for PCP. Presenters handbook HIV/AIDS and Chinese Medicine II, San Francisco, July 22-24, 1994. 4. Levander DA, Ager Al, Morris VC and May RG. Quinghaosu, dietary vitamin E, selenium, and cod-liver oil: effect on the susceptibility of mice to the malarial parasite Plasmodium yoeli. American Journal of Clinical Nutrition 1989;50:346-352. 5. Meshnick SR, Yang Y-Z, Lima V, et al. Iron-dependent free radical generation from the antimalarial agent artemisinin (quinghaosu). Antimicrobial Agents and Chemotherapy 1993;37(5):1108-1114. 6. Weinberg GA. Iron chelators as therapeutic agents against Pneumocystis carinii pneumonia. Antimicrobial Agents and Chemotherapy 1994;38(5):997-1003. 7. Haque S, Khan I, Haque A and Kasper L. Impairment of cellular immune response in acute murine toxoplasmosis: regulation of interleukin 2 production and macrophage- mediated inhibitory effects. Infection and Immunity 1994;62(7):2908-2916. 8. Hien TT and White NJ. Quinghaosu. Lancet 1993;341:603-608. F. Oral ganciclovir, eye implants and other therapies for CMV * BACKGROUND As doctors in North America have gained experience treating and preventing some of the infections seen in AIDS, patients are living longer than when the epidemic first appeared. As patients survive longer with "very low CD4+ cell counts", they can develop infections that were not commonly seen at the start of the epidermic. The sight-threatening infection CMV retinitis is increasingly being diagnosed in North American patients with AIDS. That virus can also cause ulcers in the throat and intestines, as well as infecting nerve cells inside and outside the brain. In a few patients CMV can cause pneumonia. Standard treatment for CMV is intravenous ganciclovir or foscarnet. These drugs have side effects and CMV can become resistant to them. Details about standard therapy for CMV infection appear in TreatmentUpdate 56. We now report on new options for managing CMV infection. * ORAL GANCICLOVIR Researchers in the USA treated subjects who had CMV retinitis with a 2 or 3 week course of intravenous ganciclovir. As maintenance, some subjects received oral ganciclovir 1 g three times daily. On average, subjects given oral ganciclovir had worsening retinitis "5 to 12 days earlier than [subjects] who received [intravenous] ganciclovir." (In this trial doctors made decisions about the effectiveness of the therapy by looking at photographs of the part of the eye damaged by CMV: the retina. Researchers consider decisions made by judging photographs to be more 'objective' than finding out what patients can or cannot see on eye charts). The difference between the 2 groups in the amount of time for retinitis to develop was not statistically significant. 50% of patients were protected from worsening retinitis for between "32 and 45 days" when treated with intravenous ganciclovir or foscarnet. In the USA, the FDA has approved the use of 1 g oral ganciclovir 3 times daily as "maintenance treatment" for CMV retinitis once patients have first received treatment with intravenous ganciclovir or foscarnet. In a future issue of TreatmentUpdate we will present data from a study of oral ganciclovir in the EU. * ORAL GANCICLOVIR-PREVENTION FOR SOME In other experiments, researchers in the USA found that some subjects with less than 100 CD4+ cells given oral ganciclovir were less likely to develop CMV disease than others given placebo (an inactive therapy). The following subjects developed CMV disease: - 31% on placebo - 17% on oral ganciclovir Thus despite receiving oral ganciclovir, a large proportion of subjects (nearly 60%) developed CMV disease (mostly retinitis) anyway. Researchers think that the high rate of breakthrough may be due to: - poor absorption of oral ganciclovir - virus became resistant to the drug - subjects may not have taken their drug as directed. Side effects seen in subjects receiving oral ganciclovir included bone marrow damage and low blood levels of certain white blood cells and platelets. In the USA, the use of oral ganciclovir to prevent symptoms of CMV infection will cost at least $39/day US. At this time we do not have data on quality of life and survival from subjects in this study. * EYE IMPLANTS-RISKS AND BENEFITS In TreatmentUpdate 56 we report results from a study of slow release pellets of ganciclovir placed inside a device (commonly called implants) in the eyes of subjects. The advantages of the implant over standard therapy can include: - high concentrations of drugs in the eye - no bone marrow or kidney damage - less risk of bacterial infections - less frequent blood work - possible improved quality of life Against these advantages there are potential disadvantages: - $5,000 per implant every 6 months - complications from surgery Indeed one researcher warns that "[eye surgeons] with less surgical skill or experience may have higher complication rates, and it must be recognized that these complications can have a disastrous impact on vision". * EYE IMPLANTS AND SURVIVAL As one researcher notes, "there are no data directly comparing survival of subjects receiving the [eye implant] with others receiving intravenous therapy for CMV retinitis". In the study on the eye implant, 50% of subjects survived for about 10 months. In another study where subjects received "intravenous maintenance ganciclovir", half of them survived for about 9 months. In another study, 50% of subjects receiving intravenous foscarnet survived for between 13 and 14 months. * CIDOFOVIR-INTRAVENOUS Preliminary results from trials of intravenous cidofovir (HPMPC; Vistide(tm)) suggest that "5 mg/kg given weekly for 2 weeks, then once every 2 weeks" appears to stop further damage to the eye. * CIDOFOVIR-LIPOSOMES Researchers in the USA have made tiny spheres of fat (called liposomes) containing high concentrations of HPMPC (1 mg). Injected into the eyes of rabbits infected with a herpes virus, the liposomes provided prolonged protection from eye damage, lasting between 5 and 8 months. The doctors who made the liposomes were not working for Gilead Sciences which has a monopoly on the use of HPMPC for treating CMV infections in humans. See this issue of Treatment Update for an article on eye injections of HPMPC. * ANTIBODIES AGAINST CMV Giving subjects who receive transplanted organs (who also receive immunosuppressive drugs) high doses of intravenous anti-CMV antibodies seems to reduce the incidence of CMV disease. In subjects with AIDS these antibodies have not yet provided benefit. * OTHER THERAPIES Research continues with other drugs such as "anti-sense" compounds, specially designed anti-CMV antibodies, and eye injections of ganciclovir, foscarnet or cidofovir (see pages 11-13 of this issue for details on cidofovir). REFERENCES: 1. Polis MA and Masur H. Promising new treatments for cytomegalovirus retinitis. Journal of the American Medical Association 1995 ;273(18):1457-1459. 2. Besen G, Flores-Aguilar M, Assil KK, et al. Long term therapy for herpes retinitis in an animal model with high-concentrated liposome-encapsulated HPMPC. Archives of Ophthalmology 1995;1 13:661-668. G. Cidofovir (HPMPC) for CMV-safety/toxicity * BACKGROUND Under development for the past 5 years, cidofovir (HPMPC; Vistide(tm)) has recently been tested in humans for its toxicity and anti-CMV effects. This is the first of several reports on this drug. * STUDY DETAILS Researchers enrolled 31 male adults, all of whom had HIV infection. Testing of their urine revealed that they were producing CMV. Half of the subjects had a CD4+ cell count of 61 cells. No subjects had serious CMV infection in their eyes or other parts of their body. In this study subjects received various doses and schedules of cidofovir, ranging from 1/2 mg/kg twice weekly to 10 mg/kg twice weekly. Some subjects also received the drug probenecid to reduce kidney damage caused by cidofovir. * RESULTS In general, the higher the dose of cidofovir the more likely the production of CMV would decline. As no subjects had serious CMV infection in this study the researchers were not sure which dose was best. Preliminary results from other experiments suggest that injection of cidofovir into the eyes of subjects with CMV retinitis protects them from losing their vision. * FOCUS ON KIDNEY DAMAGE The most serious problem caused by cidofovir was kidney damage. Technicians detected increased levels of protein and sugar in the urine of subjects who had kidney damage. As those subjects continued to receive cidofovir, kidney damage increased; even greater amounts of protein and sugar were lost in the urine while blood levels of important ions (phosphates, bicarbonates) fell. As well, blood levels of creatinine, produced when kidney cells break down, increased to over 2 mg/dL. There seemed to be a trend in the process of kidney damage; protein appears in the urine before sugar. Subjects receiving cidofovir 1 mg/kg did not have "significant [kidney damage]". By that statement, the researchers meant that blood levels of creatinine did not rise above 2 mg/dL. Subjects who received doses of cidofovir 3 mg/kg or more had various degrees of kidney damage. Samples of kidney cells taken from subjects receiving 3 mg/kg or 10 mg/kg revealed severe damage, similar to that seen in earlier animal experiments with cidofovir. * REDUCING KIDNEY DAMAGE To reduce kidney damage researchers gave subjects the drug less frequently. As well, some subjects received the drug probenecid. Thus, subjects could tolerate more cidofovir while their blood levels of creatinine did not rise above 2 mg/dL, nor did their blood levels of ions fall. Giving subjects extra saline before they received cidofovir appeared to protect some subjects from kidney damage. * A NOTE ON PROBENECID Probenecid is a sulpha drug that doctors sometimes use to maintain high levels of certain drugs, such as penicillin. In some studies in the late 1980s, doctors gave their patients probenecid to keep blood levels of AZT high. Some of those patients were told to reduce their dose of AZT by as much as 50%. In the experiments with cidofovir, researchers gave subjects probenecid to protect their kidneys from damage and in most cases it did. * REDUCING THE TOXICITY OF PROBENECID Since some people with HIV/AIDS cannot tolerate sulpha drugs, it is not surprising that some subjects in this study had allergic reactions when given probenecid including nausea, rashes and vomiting. To make subjects withstand the allergic reactions, the study doctors gave some subjects antihistamines. To others, the doctors first gave small doses of probenecid that were later increased over three weeks. *O DESENSITIZATION For the first dose, doctors gave the subjects "10 mg, increased by 10 mg/kg on days 2 to 5, 20 mg/day on days 6 to 10, 100 mg on day 11 and 250 mg/day on days 12 to 18". To reduce 'upset stomach', subjects were eventually told to take the drug "after meals". Use of probenecid "did not appear to [weaken] the anti-CMV effect of cidofovir". Subjects receiving the 3 mg/kg dose of cidofovir and who were also taking probenecid had a delay in the time it took to suppress production of CMV (from 7 to 27 days). * SYMPTOMS One subject who had a herpes lesion near his rectum which did not heal despite receiving acyclovir had his lesion heal when he started to use cidofovir at 5 mg/kg week. Another subject with 'oral hairy leucoplakia' on his tongue had that infection clear after his first dose of cidofovir also at 5 mg/kg/week. Cidofovir used in this experiment was supplied by Gilead Sciences, Foster City, California. REFERENCES 1. Lalezan JP, Drew WL, Glutzer C, et al. (S)-1-[3-hydroxy-2-phosphonlmethoxy)propyl] cytosine (cidofovir): Results of a phase I/II study of a novel antiviral nucleotide analogue. Journal of Infectious Diseases 1995;171:788-796. H. Cidofovir-anti-CMV activity * STUDY DETAILS In this study, researchers recruited 21 male HIV-infected subjects, at least half of whom had a CD4+ cell count of 39 cells. Subjects did not have symptoms of CMV infection but were all producing CMV, detected in their urine samples. Moreover, blood samples from 15 subjects also had CMV. As with our earlier report, subjects received a range of doses and schedules of cidofovir(HPMPC; Vistide(tm)). To reduce kidney damage, doctors gave some subjects 1 litre of saline before they started to receive cidofovir. All subjects receiving cidofovir 5 mg/kg/week or more took 2 g probenecid 3 hours before receiving the cidofovir and 1 g at two and eight hours after they received cidofovir. * RESULTS-TOXICITY The most common side effect of HPMPC was kidney damage. Technicians first detected increased protein and sugar in the urine samples of subjects; indicating that kidney damage had occurred. Seventeen subjects had protein detected in their urine samples at some point during the study. In most subjects, the kidney damage was temporary. One subject, who also received the anti-HIV drug d4T (stavudine), developed some heart damage during the study. When he stopped taking both drugs, he recovered after several months. * SERIOUS SIDE EFFECTS Two subjects developed skin rashes when given probenecid. Doctors gave these subjects Tylenol and the antihistamine Benadryl(R). Despite these measures, one subject had a severe reaction and went into shock. He later recovered and never again received probenecid. Another subject had severe nausea when given probenecid and cidofovir and left the study. * ANTI-CMV EFFECTS In this study, as the dose of cidofovir increased, production of CMV fell. Three subjects who received 5 mg/kg twice weekly "did not have detectable CMV after 3 weeks". Production of CMV did not immediately resume when these subjects stopped taking HPMPC. In other subjects, CMV could once more be detected in the urine "up to 2 months after the last dose of cidofovir." * CMV IN THE BLOOD At the start of the study, 15 subjects had blood from which CMV could be 'grown' or cultured. Despite receiving cidofovir, CMV could still be cultured from their blood samples. Indeed, 6 subjects who had 'negative' blood cultures developed 'positive' blood cultures. One subject who continued to produce CMV in his blood developed an intestinal infection from that virus 5 weeks after he stopped receiving cidofovir. Doctors treated him with intravenous ganciclovir, and 2 weeks later technicians could not culture CMV from his blood or urine samples. In another subject, CMV could be cultured from his blood samples despite receiving 7.5 mg/kg of cidofovir every three weeks. As in the previous case, after a 2-week course of ganciclovir, technicians could not culture CMV from his blood or urine. * WHAT NEXT? Results from this study suggest that cidofovir 5 mg/kg twice weekly is too toxic, while the same dose once weekly or 7.5 mg/kg every 3 weeks has potential benefit without some of the more severe risks. Probenecid can reduce the toxicity of cidofovir. Larger and longer studies of cidofovir need to be done in subjects with symptoms of CMV disease so that researchers can show possible benefits. REFERENCES: 1. Polis MA, Spooner KM, Baird BF, et al. Anticytomegalovirus activity and safety of cidofovir in patients with Human Immunodeficiency Virus infection and cytomegalovirus viuria. Antimicrobial Agents and Chemotherapy 1995;39(4):882-886. I. Eye injections-cidofovir for CMV * STUDY DETAILS All 16 subjects in this study were adults (15 males, 1 female) with AIDS, and had 'active' CMV infection in the eye despite treatment with intravenous ganciclovir and/or foscarnet. Some potential subjects with complications including eye inflammation, infection of the eye with other microbes or detached retinae were not allowed to enter the study. There were 2 stages in this study. In the first part doctors enrolled 9 subjects and used them to look for toxic effects from the eye injections while giving them intravenous ganciclovir. In the 2nd part of the study, doctors were trying to find out about the anti-CMV effects of cidofovir. As with the studies of intravenous HPMPC, most subjects in this trial received 2 g of probenecid 3 hours before having their eye injections and later, "1 g orally each at 2 and 8 hours after cidofovir injections." To inject the drug doctors used a "30 gauge needle attached to a tuberculin syringe." * RESULTS-PART 1 In the first part of the study, 9 subjects received various doses of cidofovir ranging from 10 to 100 microgrammes. Half of these subjects were monitored for about 76 days and doctors examined their eyes weekly. Three subjects had complications-"[inflamed eyes, changes of the pressure inside the eyeball]". By the end of the study, over 90% of untreated eyes had worsening damage from CMV despite continued intravenous ganciclovir. * RESULTS-PART 2 For this experiment doctors injected cidofovir into 8 eyes. About half of subjects receiving an injection of cidofovir 20 pg (microgrammes) had worsening eye damage from CMV 64 days later. No serious complications as a result of the injections occurred. * RECOMMENDED DOSE AND WARNINGS The researchers stated that in "every [subject] treated with cidofovir alone", eye damage by CMV was blocked. They "recommend and use a dose of 20 pg cidofovir" when treating their patients with CMV retinitis. They are not sure that probenecid provided any protection against eye damage caused by cidofovir. As well, while complications from eye injections were few, the researchers warn that: "[complications from eye injections] may not be entirely preventable despite [very careful and skillfill] technique, [the risk of this happening] must be [carefully explained] to any patient [thinking about eye injection] therapy for CMV retinitis." * PROBLEMS GETTING HPMPC Although originally found in plants, chemists can now make HPMPC in their labs. In the USA the company Gilead Sciences (Foster City, California) is developing cidofovir as an intravenous therapy for CMV. The HPMPC used in this study was made by researchers in Belgium because Gilead refused to supply it for the experiments with eye injections. An investigation by Jon Cohen for the journal Science suggests that Gilead refused to supply the drug because "...it wouldn't make much profit from the small, infrequent doses used in the [eye injections]." One American treatment activist said that "[a]ny effort to move forward on intravitreal treatment has been completely stonewalled by the company." A senior staff person at Gilead denies that this is the case. Gilead hopes that the FDA will approve the use of IV cidofovir for the treatment of CMV infection. The company also plans to conduct a study of injecting HPMPC into the eyes of subjects to confirm the data from this independent study. ACKNOWLEDGEMENTS: 1. We thank B. Goldberg for rapid access to this research. REFERENCES: 1. Kisch LS, Arevalo JF, De Clercq E, et al. Phase I/II study of intraviteal cidofovir for the treatment of cytomegalovirus retinitis in patients with the Acquired Immunodeficiency Syndrome. American Journal of Ophthalmology 1995;119(4):466-476. 2. Cohen J. AIDS drug: experiencing local delays. Science 1995;268:369. J. Recovery from MAC infection * BACKGROUND As the immune system weakens, people with AIDS become at risk for developing many life-threatening infections including those caused by MAC (Mycobacterium avium complex). One American doctor recently reported 1 case in the USA where his patient apparently recovered from MAC. * SYMPTOMS AND TREATMENT On his first visit to the doctor the patient had a fungal infection in the throat and 40 CD4+ cells. He then began to take AZT 500 mg/day. Two months later he was coughing and had to have some X-ray pictures of his chest taken. At first the doctor thought he had tuberculosis and prescribed anti-TB therapy, a combination of isoniazid, rifampin and pyrazinamide. Despite this treatment, he did not improve. A sample of fluid/tissue taken from a lymph node revealed that he was infected with MAC. His prescription was changed to: Cipro 750 mg/day, clofazimine 100 mg/day, ethambutol 15 mg/kg/day "and amikacin 10 mg/kg/day for 2 weeks." He continued to use rifampin 600 mg/day. * RESULTS Two months later he stopped coughing, X-ray scans suggested that the infection had not spread and blood levels of liver enzymes fell to near normal levels. The patient also gained 12 lbs. Several months later his doctor stopped prescribing clofazimine and gave him clarithromycin 2 g/day. Six months later all signs and symptoms of MAC infection cleared and he was switched to just azithromycin 500 mg/day. He later developed several parasitic infections while his chest X-ray scans and liver enzyme levels remained normal. He eventually died about 6 months after he started using azithromycin. In a investigation into his cause of death, pathologists could not find any infection with MAC. REFERENCES: 1. Farber HW. Long-term resolution of disseminated Mycobacterium avium complex infection in a patient with AIDS. Clinical Infectious Diseases 1995;20:1067-1068. K. Antifungal drugs-- warning about combinations * BACKGROUND The release of newer antifungal drugs-fluconazole and itraconazole has been welcome because of their generally lower toxicity (than existing drugs) and ease of use (swallowing tablets versus getting intravenous therapy). Doctors are reporting more cases of fungal infections that are resistant to fluconazole and itraconazole, so some are experimenting with higher doses of those drugs or using intravenous amphotericin B (AmB). Researchers in the EU are performing laboratory experiments with fungi and combinations of antifungal drugs. Results from their work suggest that using fluconazole with AmB causes the drugs to interact and weakens their antifungal effect. Other researchers have confirmed their results in experiments with animals. They suggest that in cases where patients have widespread candida infection, combination therapy with AmB and azoles (including fluconazole, itraconazole, ketoconazole) "should be avoided". Information on the treatment of some fungal infections appears in the next issue of TreatmentUpdate. REFERENCES: 1. Scheven M and Scheven M-L. Interaction between azoles and amphotericin B in the treatment of candidiasis. Clinical Infectious Diseases 1995;20:1079. III TOXICITY A. Reducing the toxicity of sulpha drugs * BACKGROUND Doctors can prescribe Bactrim/Septra (B/S) taken daily or 3 days/week for their HIV-infected patients in an attempt to prevent or delay the life-threatening lung infection PCP. HIV-infected people seem to develop more side effects to sulpha drugs than non-HIV-infected people. To reduce side effects some doctors may give their patients very small doses of sulpha drugs. Over time, the dose is gradually increased until patients can tolerate standard doses. This process of gradually giving patients increased doses of a drug so they can tolerate it is called desensitization. Researchers in the USA have been reviewing files on subjects who had tried to reduce their allergic reactions to sulpha drugs. * STUDY DETAILS The researchers reviewed data on 22 "consecutive" subjects with AIDS (19 male, 3 female) who entered a desensitization study. While taking sulpha drugs in the past, these subjects had developed severe rashes, high fever, liver damage and vomiting, among other symptoms. Eight of these went into shock within "minutes" after taking a regular dose of B/S; 5 of them had to go into an intensive care unit. The average CD4+ cell count of the subjects was about 113 cells. These subjects were supposed to receive aerosolized pentamidine but were convinced by the researchers to enter into their study on desensitization. At first subjects received very small doses of the drugs contained in Bactrim/Septra (trimethoprim and sulphamethoxazole) 0.004 mg trimethoprim and 0.02 mg sulphamethoxazole taken with a glass of water. This dose was increased ten times every hour for 4 hours. By the fifth hour subjects received a normal dose of 160 mg of trimethoprim and 800 mg of sulphamethoxazole. Doctors monitored subjects during the process so they could rescue them in the event of an allergic reaction. * RESULTS Nineteen of 22 subjects (86%) finished the desensitization protocol. The 3 remaining subjects began to vomit or have chills which cleared when treated with the drugs ibuprofen and Gravol. Of the 19 subjects, only 2 had reactions such as temporary rash and "low grade fever". One of the 19 subjects died from a bacterial infection, leaving 18 subjects for long term monitoring. * LONG TERM RESULTS Three of the 18 subjects developed side effects "within 2 weeks of desensitization". The side effects included fever and/or [macular] rash, so they stopped taking B/S. According to one of the study doctors, "the remaining 15 subjects, including 6 of the eight [subjects] who [went into shock] before undergoing desensitization and the 2 who had mild reactions during the procedure, successfully tolerated long term use of [B/S] as [preventative therapy] for PCP". Of the 15 subjects, "13 had no side effects to [B/S], while 2 others had [temporary] rashes" one week after desensitization. Over an average monitoring period of 14 months, no subject developed PCP. The researchers also noted that during the desensitization process no subject "required hospitalization, emergency-department care, or medications other than ibuprofen or [Gravol] for reactions to [B/S] during or [after] desensitization". * OVERALL RESULTS According to the study doctors, results from this review show that "71% of 21 evaluable [subjects] were successfully desensitized". They also did not try and "re-desensitize" subjects who had been unable to become desensitized before this study and who used their desensitization protocol. One of the features of their protocol is that it is quick--5 hours--and simple, unlike many other protocols. Future issues of TreatmentUpdate will have other reports on desensitization. REFERENCES: 1. Gluckstein D and Ruskin J. Rapid oral desensitization to trimethoprim-sulphamethoxazole (TMP-SMZ):use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ. Clinical Infectious Diseases 1995;20:849-853. CORRECTION In TreatmentUpdate 57, under the subheadline "AZT: Delivery & Dose" (page 6, sentence 4), a quote was omitted. The sentence should read: AZT is supposed to work by interfering with the viral enzyme RT (reverse transcriptase): "AZT prevents the infection of new cells, but not the production of [HIV] from cells already infected". REFERENCE: Nowak, MA, Bornueffer S, Loveday C. et al. EGV results in the frame: results confirmed. Nature 1995;375:193. CORRECTION: The wrong issue number was given in the section titled "A warning about thalidomine", in TreatmentUpdate 59. Further information about thalidomine can be found in TreatmentUpdate 32. We apologize for these errors and any inconvenience they may have caused. Copyright (c) 1995 - CATIE. Distributed by AEGIS, your online gateway to a world of people, knowledge, and resources. 714.248.2836 * 8N1/Full Duplex * v.34+