Subject: PCP; Stockholm Pt 2; Pentamidine Date: Aug 30 1988 (1021 lines)) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Volume 2 Number 6 August 30, 1988 [Footnotes are enclosed in triple quotation marks: ((()))] In this issue: Pneumocystis carinii Pneumonia (PCP) Notes from Stockholm: Part 2 Aerosolized Pentamidine Update In Brief New Studies ............................. GMHC Has Moved! The Department of Medical Information has moved to a new space. Please address all correspondence to: GMHC, Department of Medical Information, 129 West 20th Street, NY, NY 10011. ............................. Pneumocystis Carinii Pneumonia (PCP) by Don Shewey History Pneumocystis carinii pneumonia (PCP) is the leading cause of death in people with AIDS. According to the National Institute of Allergy and Infectious Diseases (NIAID), almost 70% of AIDS patients will develop PCP at some point in their illness. AIDS patients account for 98% of all cases of PCP in the United States, and 67% of new AIDS cases are diagnosed because of PCP ((( NIAID Backgrounder ))). Pneumocystis carinii is a unicellular organism that is thought to be a parasite and infects the lungs of humans and many animals. Recent research suggests that pneumocystis may, in fact, be a fungus. It is present at diagnosis in about 60% of patients with AIDS and occurs at some time during life in 80-85% ((( Mills, J. Pneumocystic carinii and Toxoplasma gondii Infections in Patients with AIDS. Reviews of Infectious Diseases 8: 1001, 1986. ))). PCP occurs almost exclusively in severely immunocompromised patients, both those with AIDS and other immune deficiencies. Subclinical asymptomatic infection occurs in the majority of normal people early in life, and it is thought that the organism remains dormant in the healthy population. Presumably, in AIDS, pneumonia results from reactivation of the latent infection. Hence, it is not considered to be transmissible from person to person. The symptoms of PCP include: dyspnea (shortness of breath), non-productive cough, fever, wheezing, and a "catching" sensation in the chest upon deep inhalation. Lab tests are becoming increasingly sophisticated for diagnosing PCP, as is treatment of the infection, resulting in remarkable survival rates. This article summarizes the pertinent information on PCP. PCP is said to be a disease of the antibiotic age in which immune-deficient individuals can be kept alive. Epidemics with PCP were not seen prior to World War II and the advent of antibi- otics ((( Dutz, W. et al. Marasmus and Pneumocystis carinii Pneumonia in instiutionalised infants. Z. Kinderheilk. 117: 241, 1974 ))). PCP was first described in South America in 1909. Since it's difficult to diagnose clinically (diagnosis requires microscopic exmination of lower respiratory secretions or lung tissue), it was only reported from autopsies. Not much is known about the life cycle and metabolism of PCP. Laboratory experimentation is very difficult, because it requires prolonged immunosuppression of pathogen-free rats (attempts to infect rats with p. carinii from human lungs have failed), and the organism survives in the test tube for a very limited period of time. Its life cycle involves two basic forms: trophozoites (an immature form) and mature, thick-walled cysts. Actual pneumonia involves an initial phase in which cysts become visible within lung cells; a second phase in which parasitic replication increases and trophozoites are evident; and a final phase in which congestion and inflammation appear within the alveoli (lung sacs) and alveolar walls. This sequence of PCP infection has been documented previously in severely malnourished infants and in children and adults who have diseases or are being treated with drugs that suppress the immunologic system. ((( Luce, JM, and Hopewell, PC. Pulmonary complications of AIDS. Cardio- vascular Med December 1984, p. 945 ))) The course of the disease may be more subtle and chronic in people with AIDS than in those without. ((( Hughes, WT Pneumo- cystis carinii pneumonitis. NEJM 317: 1021, 1987 ))) In one study the median duration of symptoms at the time of presentation was 28 days in PWAs, 5 days in those who didn't have AIDS. ((( Kovacs, JA et al. Pneumocystis carinii pneumonia: A comparison between patients with the Acquired Immunodeficiency Syndrome and Patients with Other Immunodeficiencies. Ann Internal Med 100: 663, 1984))) Also, the response to treatment is slower and relapse occurs more frequently with AIDS. Why PCP presents as a more subtle, slowly progressive pneumonia and why reactions to treatment are so com- mon remain a mystery -- perhaps AIDS permits a different host- parasite relationship from that in patients treated with immu- nosuppressive drugs. Diagnosis The earlier PCP is detected, the better the patient's prog- nosis for effective treatment. The presenting symptoms often resemble less serious respiratory conditions, and it is important to establish the diagnosis and begin therapy promptly. Currently, PCP is most frequently diagnosed by bronchoscopy -- that is, inserting a bronchoscope into the lungs and either irrigating the lungs to obtain fluid samples (lavage) or using the bronchoscope to obtain a tissue sample (biopsy). (As recently as 1980, open- lung biopsy -- a surgical procedure to remove a piece of lung through the chest wall -- was thought to be more accurate than bronchoscopy for diagnosing PCP, before the advent of bronchoal- veolar lavage. Today open-lung biopsy is recommended in less than 5% of cases, because it's more risky and costly.) Transbronchial biopsy is slightly more sensitive than lavage. In very sick patients, bronchial lavage is at least equally reli- able; it's also faster, less costly, and better tolerated. ((( Rorat, E et al. Diagnosis of Pneumocystis carinii pneumonia by ctyologic examination of bronchial washings. JAMA 254: 1950, 1985 ))) Treatment of patients with possible PCP would be facilitated by the availability of a rapid, reliable non-invasive technique for establishing diagnosis. Although bronchoscopy has been found to be safe and sensitive, its potential complications, high cost, and discomfort dissuade many physicians from subjecting patients to it. To justify invasive procures, screening procedures are helpful. The most frequent abnormality in pulmonary testing is a decreased single-breath diffusing capacity for carbon monoxide (DLCO) -- effective in screening for lung involvement in patients with minimal symptoms. Gallium scanning represents another non- invasive screening mechanism. Both have a 90% sensitivity in detecting an infection, but neither is specific for PCP. If either is abnormal, proceeding with bronchoscopy is advisable. If both are normal, the general course is to observe the patient and repeat tests in a week if symptoms progress. A definitive diagnosis can be made only by lung specimens, either bronchial washings or biopsy done during bronchoscopy. The only absolute contraindication to transbronchial biopsy is the presence of an uncorrectable coagulation problem, and many patients on respirators tolerate the procedure poorly. Recent studies show that examination of induced sputum is a rapid, sen- sitive, and inexpensive method for diagnosing PCP, using a stain- ing technique called "indirect immunofluorescence". After a vigorous gargle with water to reduce contaminating oral debris, patients inhaled a mist of nebulized 3% saline, generated by an ultrasonic nebulizer, for 5-15 minutes. This induces a vigorous, deep cough. In 23 of 25 patients from whom sputum was obtained before a scheduled bronchoscopy, PCP was diagnosed. In examining sputum, the staining technique matters. "Diff- quik" stains not only P. carinii but also host and microbial cells and other debris; toluidine blue O stains yeast in addi- tion. Indirect immunofluorescence is the most sensitive; it's practical, economical and easily adaptable by most labs. Last week, Meridian Diagnostics, Inc., a Cincinnati-based firm, announced that diagnostic kits using the indirect immunofluores- cence technique will be available by mid-September. Interested physicians may contact Jerry Ruyan at Meridian at (513) 271-3700. This important development will obviate the need for bronchoscopy in a large number of cases, and will cost about $6 per patient, a substantial reduction from the $600 bill typically attached to a bronchoscopy. Examining induced sputum works best with individu- als at risk for HIV infection, with a non-productive cough, and with a chest x-ray showing characteristic markings. The diagnos- tic yield of sputum studies in other immunosuppressed patients was only 5-10%; with AIDS, 61%. If a sputum specimen is negative for P. carinii or if a patient positive for P. carinii as detected in sputum responds poorly to therapy, bronchoscopy should be strongly considered to assess the possible presence of other infections or tumors. Some physicians feel that the urgency to treat PCP is so overwhelming that an empirical (presumptive) diagnosis is warranted even when sputum analysis and bronchoalveolar lavage are negative. ((( Moskowitz R et al. Empirical diagnosis of Pneumocystic carinii pneumonia. JAMA 259: 2849, 1988 ))) And there is evidence to support this theory. One study in England treated 73 HIV-positive men for PCP; on the basis of subsequent bronchoscopies, it was found that empirical therapy was correct. ((( Miller, RF, et al. Empirical therapy for presumed PCP is justified. IV Intn'l Conf on AIDS, Stockholm, 1988, #7162 ))) Another study found that shortness of breath combined with elevated serum LDH (over 220) had a 94% predictive value for PCP. ((( Grover, Steven,, et al. The Clinical utility of serum lactate dehyrogenase (LDH) in diagnosing PCP in hospita- lized AIDS patients. IV Intn'l Conf on AIDS, Stockholm, 1988, #7143 ))) It has also been suggested that T4 lymphocyte counts may be useful in early diagnosis of PCP; one study found that patients with T4-cell counts greater than 255 rarely have PCP. ((( Masur, H, et al. peripheral CD4 lymphocyte counts are predic- tive of the cause of pneumonitis in HIV infected patients. IV Intn'l Conf on AIDS, Stockholm, 1988, #7142 ))) Other physicians feel that PCP should be confirmed by iden- tification of organisms. For people with AIDS, other causes of pneumonia are common. PCP can easily be mistaken for either cytomegalovirus (CMV) or M. avium intracellulare (MAI), both of which have radically different therapies from PCP. One indicator to distinguish MAI from PCP is that the former often causes lym- phadenopathy. Blood cultures for MAI may take several weeks to become positive. Bronchoscopy is most useful for diagnosing PCP; less useful for CMV; even less for MAI; not at all useful for KS ((( Two tests, used jointly, have high diagnostic value for lung pathology in AIDS. Infectious Diseases, Feb/Mar 1985, p. 26 ))) A procedure called "Lung 99mTc DTPA transfer" distinguishes between PCP and other bacterial infections with high sensitivity and specificity. Easy and cheap, this procedure may someday obviate the need for bronchoscopy in many high-risk patients. ((( Raffi, F, et al. Early detection of asymptomatic PCP with 99mTc-DTPA aerosol lung clearance. IV Intn'l Conf on AIDS, Stock- holm, 1988, #7148 ))) Treatment Studies have shown that the single most important indicator in survival among people with AIDS was the patient's initial response to anti-PCP therapy, emphasizing the importance of the clinician's assessment during the first seven days in estimating the ultimate length of survival. ((( (48)48. Andiman, WA, et al. Prognostic indicators of survival in AIDS patients with PCP: a biostatistical analysis. III Intn'l Conf on AIDS, Washington, 1987, #TP. 150 ))) The assessment of new or adjunctive treatments for PCP has been hampered by the lack of an animal model that reliably mimics human disease. The cause of respiratory distress and the acute respiratory distress syndrome in PCP is unclear; the condition may represent toxic effect of the organism, an ex- aggerated inflammatory response, or both. If local inflammation plays an important part, steroids may well be recommended. Though not recommended for routine or accepted therapy, some feel they should be tried in refractory (non-responsive) cases. ((( Lambertus, MW, and Goetz, MB. Treatment of pneumocystis pneumonia in AIDS. NEJM 318: 988, 1988 ))) The two drugs in general use, Bactrim and pentamidine, are equally effective in 75% of cases. Bactrim is less toxic, has fewer side effects, and is available in oral as well as IV forms. Both have high rates of adverse ef- fects. Other drugs currently being investigated include: Dapsone (alone or with trimethoprim); fansidar; trimetrexate; and aerosol pentamidine. Dr. Joseph Sonnabend has been eloquent in pointing out that, in approaching an illness for which there is no cure, two broad areas must be addressed. The first concerns the management of the patient and involves all measures at the physican's disposal to reduce suffering and prolong life. The second deals with the study of experimental approaches which may lead to a cure. The former area of concern should never be abandoned in pursuit of the latter. In other words, attention to the patient's immediate needs must be the first concern of the physician, and experimen- tal treatments pursued after that. ((( Sonnabend, Joseph. More thoughts on preventing PCP. PWA Coalition Newsline ))) Most PCP patients will require supplemental oxygen. Intubation and mecha- nical ventilation should be undertaken only as a last resort, but should be discussed with the patient very early in hospital course, as cognitive function may later by impaired by hypoxia, drugs, or neurologic manifestations of AIDS. Bactrim Since the late 1970s, Bactrim (or the equivalent drug Sep- tra) has been used first for treatment of PCP. The generic name for these drugs is either trimethoprim-sulfamethoxazole (TMP/SMZ) or co-trimoxazole. The usual practice is to begin treatment with 20 mg/kg of TMP and 100 mg/kg of SMZ intravenously, divided into four doses per day. If the patient improves, oral therapy can be tried (although gastrointestinal intolerance is common). Adverse reactions are often noted: altered taste, nausea with occasional vomiting, itching, rash (with or without fever), and leukopenia (lowered white cell count). Up to half taking it experience toxic effects; around 17% have to stop. Leucovorin calcium may help prevent bone marrow suppression and decrease potential for skin toxic reactions. Pentamidine If the patient deteriorates on TMP/SMZ (Bactrim), the common response is to try pentamidine (4 mg/kg per day, in one dose); intramuscular administration is very painful, so most find a slow intravenous infusion over 2 hrs. to be preferable. Pentamidine was discovered to have antiprotozoal activity in 1938. Pentami- dine has been used since the 1940s to treat a variety of proto- zoal infections. In 1965, PCP with associated immunoglobulin deficiencies was "cured" by a combined administration of gamma- globulin and pentamidine. Now pentamidine is most commonly used for PCP. At times it has life-threatening adverse reactions. Among these are leuko- penia, hepatitis, kidney problems and severe reactions of low blood sugar (hypoglycemia). ((( Waskin H et al. Risk factors for hypoglycemia associated with pentamidine therapy for pneumocystis pneumonia. JAMA 260: 345, 1988 ))) Nonetheless, pentamidine serves as important alternative to Bactrim in treating PCP pa- tients with a history of allergy to sulfa drugs or who simply don't respond to Bactrim. While intravenous PCP is associated with side effects in over 50% of AIDS patients, a study of in- haled (aerosolized) pentamidine in patients with mild PCP showed efficacy and a tolerable incidence of adverse effects. Further study is being made. ((( Golden, JA, et al. Inhaled pentamidine as exclusive therapy for PCP in AIDS. III Intn'l Conf on AIDS, Washington, 1987, #TP. 217 ))) Trimetrexate Adverse reactions occur in at least 40% of AIDS patients treated for PCP with pentamidine or Bactrim. The drugs Trimetrexate (TMX) and leucovorin has been shown safe and effec- tive as initial treatment for those not responding to standard therapies. TMX, a new anticancer agent created in 1969, was found to be 1500 times more potent as an inhibitor of the P. car- inii protozoa than trimethoprim. ((( Allegra, CJ, et al. Trime- trexate for the treatment of Pneumocystic carinii pneumonia in patients with the acquired immunodeficiency syndrome. NEJM 317: 978, 1987 ))) Trimetrexate works by interfering with the body's utilization of a group of vitamins called folates. Fo- lates are essential to metabolic process in both PCP organisms and in human cells. It's currently given intravenously once a day for 21 days. Leucovorin is given 4 times a day for 24 days, either by vein or orally. ((( NIAID Backgrounder ))) Leucovorin can selectively rescue host cells from the toxic effects of TMX. The dosing schedule is not yet certain, but one study of 52 AIDS patients showed that the best combination of TMX and leucovorin was 45/80 mg. ((( Sattler, F. et al. Trimetrexate and leucovorin for PCP. IV Intn'l Conf on AIDS, Stockholm, 1988, #7177 ))) Studies of oral trimetrexate are also underway. ((( Rogers, P, et al. Bioavailability of oral trimetrexate in patients with ac- quired immunodeficiency syndrome. Antimicrobial Agents and Che- motherapy 32: 324, 1988 ))) Although considered experimental, patients who experience severe reactions to conventional therapy (or simply aren't responding to conventional therapy) may qualify to receive TMX under a "Treatment IND". A physician may contact NIAID and receive the medication free of charge by express mail delivery if the patient meets the criteria for participation in the FDA- approved Treatment IND protocol. The number is 1-800-426-7527 (in Michigan, 1-800-833-0014), between 8am and 8pm EST. Other treatments Corticosteroids can prevent deterioration and avoid mechani- cal ventilation of patients with moderately severe PCP. ((( Heise, W., et al. Steroids in trreatment of severe PCP in AIDS. IV Intn'l Conf on AIDS, Stockholm, 1988, #7163. Montaner, JSG, et al. Oral corticosteroids (CS) for moderately severe PCP in AIDS. IV Intn'l Conf on AIDS, Stockholm, 1988, #3668 ))) An accelerated recovery of respiratory insufficiency was seen in PCP patients treated with steroids in addition to co-trimoxazole, without severe side ef- fects. Eflornithine (alphadifluoromethylornithine), sometimes called DFMO, has been investigated as a treatment for PCP. Effec- tive in four out of ten patients, it caused severe gastrointes- tinal disturbances and bone marrow suppression. ((( Gilman, TM, et al. Eflornithine treatment of pneumocystic carinii pneumonia in AIDS. JAMA 256: 2197, 1986. Goldstein, JA, and Brennessel, DJ. Eflornithine hydrochloride (DFMO) in the Therapy (rx) of PCP in AIDS. II Intn'l Conf on AIDS, Paris, 1986, #295. Diete- rich, DT, et al. Eflornithine Treatment of resistant PCP in AIDS patients. II Intn'l Conf on AIDS, Paris, 1986, #298 ))) The combination of the drugs primaquine with clindamycin has proven effective in preventing infection with PCP in rats; it shows promise for humans. ((( Queener, SF, et al. Activity of Clindamycin with primaquine against pneumocystis carinii in vitro and in vivo. [abstract] Antimicro. Agents Chemoth 32: 807, 1988 ))) Prophylaxis Prophylaxis against PCP for people with AIDS is urgent. Successful PCP therapy does not eradicate the organism from the lung tissue. 30-40% who recover from PCP will have one or more recurrent episodes. Therapies that have met with apparent suc- cess include oral Bactrim, ((( Fischl, MA, et al. Safety and ef- ficacy of Sulfamethoxazole and Trimethoprim chemoprophylaxis for Pneumonia carinii pneumonia in AIDS. JAMA 259: 1185, 1988 ))) Dapsone, Fansidar, and aerosolized pentamidine. For those who can't tolerate prophylaxis or fail it, data suggests that de- spite toxicity of available agents, most recurrent bouts can still be successfully treated. ((( Hollander, H, et al. Recur- rent AIDS-related PCP: frequency, outcome and prevention. II Intn'l Conf on AIDS, Paris, 1986, #283 ))) An increased preva- lence of adverse reactions to Bactrim often complicate use of this agent as prophylaxis ((( Kaplan, LD, et al. Trimethoprim- sulfamethoxazole prophylaxis of PCP in AIDS. II Intn'l Conf on AIDS, Paris, 1986, #299 ))) although prior reactions to IV therapy may not be a contraindication to subsequent oral pro- phylaxis. ((( Shafer, RW. Successful prophylaxis of PCP with trimethoprim-sulfamethoxazole in AIDS patients with previous allergic reactions. II Intn'l Conf on AIDS, Paris, 1986, #301 ))) Patients with KS have shown good efficacy and tole- rance for Bactrim. Some studies have shown that Bactrim three days a week is as effective as every day; this causes less fre- quent fungal infections and costs less. Also it may be more beneficial to those who can't tolerate daily doses. ((( Hughes, WT, et al. Successful intermittent chemoprophylaxis for Pneumo- cystic carinii pneumonitis. NEJM 316: 1627, 1987. Gilman, TM, et al. Trimethoprim-sulfamethoxazole pharmacokinetics in pati- ents with AIDS. IV Intn'l Conf on AIDS, Stockholm, 1988, #7175 ))) To combat hypersensitivity to Bactrim, oral desensi- tization has been recommended. ((( Gluckstein, Dan, et al. Oral desensitization (OD) to trimethoprim-sulfamethoxazole in hyper- sensitive AIDS patients. IV Intn'l Conf on AIDS, Stockholm, 1988, #7176 ))) Dapsone also appears to be an effective PCP prophylaxis. In a study of 156 patients, only one taking dapsone developed PCP, while 14 of 19 patients who refused dapsone deve- loped PCP. Complications included nausea, skin rash, and anemia: 25% of patients required one or more transfusions of red blood cells. ((( Metroka, CE, et al. Successful chemoprophylaxis for PCP with dapsone in patients with AIDS or ARC. III Intn'l Conf on AIDS, Washington, 1987, #THP. 231 ))) Investigators have found that the drug Fansidar significantly reduces the recur- rence of PCP ((( Hardy, D et al. Long-term follow-up on fansi- dar prophylaxis for PCP in patients with AIDS. III Intn'l Conf on AIDS, Washington, 1987, #THP. 232. Vierira, J. Fansidar pro- phylaxis of PCP in asymptomatic HIV-positive persons and persons with ARC. III Intn'l Conf on AIDS, Washington, 1987, #TP. 221 ))) and report that the drug was well tolerated. However, recent re- ports of severe allergic reactions to Fansidar, some of them fa- tal, have prompted many physicians to abandon it, at least tem- porarily. Further studies of Fansidar are underway. In a trial of monthly intravenous pentamidine for prophylaxis, pentamidine was still detectable in the blood after a month. Further studies are in progress. ((( Rehm, SJ, et al. Blood levels of pentamidine in AIDS patients receiving monthly prophylaxis. III Intn'l Conf on AIDS, Washington, 1987, #WP. 222 ))) The most promising use of pentamidine for PCP prophylaxis, however, is the use of aerosol to deposit the drug directly in the lungs, where it is needed. Preliminary results are very encouraging, and are reported in a related article "Aerosolized Pentamidine Update" in this issue. AZT has not been shown to prevent recurrences of PCP, although the recurrences seem to be milder. ((( Campbell, SW, et al. Com- parison of second episodes of PCP between AIDS patients treated and not treated with AZT. IV Intn'l Conf on AIDS, Stockholm, 1988, #7139 ))) Summary Over the past six years, there has been a remarkable dearth of properly designed, randomized, blinded, controlled, and bios- tatistically sound clinical studies to evaluate prophylactic and therapeutic drugs for PCP and their adverse effects. Further studies of all the drugs mentioned here are needed as well as characterization of the natural course of PCP in AIDS. It is to be hoped that the urgency of the problem will be sufficient to foster rapid, definitive studies and preclude inconclusive and subjective reports. The Stockholm AIDS Conference: Part 2 This is the second part of a report on the Fourth Interna- tional Conference on AIDS held in Stockholm June 12-16. The last issue of Treatment Issues focused on AL721 and Dextran sulfate. In this issue, we report on AZT, the AZT/Acyclovir combination and other therapies. Because of the large number of references, the article is not footnoted in our typical format; instead, abstract numbers appear in parentheses rather than at the bottom of the page. Anyone wishing to read or photocopy original abstracts may do so by appointment at the Department of Medical Information. AZT -- general comments There were over 130 papers presented on AZT, and in many respects, the Fourth International Conference on AIDS seemed more like a conference on AZT. Many of the studies were not of the best caliber: some involved only a handful of patients or were of insufficient duration to draw firm conclusions. We have focused on the larger, more authoritative trials. Numerous papers were presented describing the experiences of physicians here and abroad treating patients with AZT. These kinds of stu- dies are significant because they serve as corroboration of the conclusions previously published on the drug. Unfortunately, though, most of the studies were of short duration, i.e. less than 20 weeks. At North Shore University Hospital (#2607), there was a 90% survival after 6 months of AZT therapy, which is com- parable to published results from the original AZT study. Researchers in Frankfurt, Germany (#3612) reported even better 6-month survival statistics on 97 patients -- over 95% survival. Burroughs Wellcome's extended study of 4,805 AIDS patients (#3605) described a "70-88% [9-month survival] depending on the patients clinical condition at the time of drug initiation." The two-year survival was reported as 47%. Comparing these figures with what we know about AIDS survival with no therapy, there seems to be little room for doubt that AZT "works" in prolonging survival in patients with AIDS. All studies agree that AZT does not appear to improve immune function as measured by T4-cell counts, and it is clear that AZT does not totally eliminate HIV from the body. AZT does not appear to be effective in infected macrophages, a blood cell which may thus act as a reservoir of infection in the body. As always, toxicity was observed as a major problem with AZT. Interestingly, experiences with toxicity varied widely, probably reflecting differences between the general state of health of participants. Studies agree that patients starting out anemic, with low T4 counts, or low white cell counts were more likely to run into trouble with AZT. But the frequency of seri- ous side effects reported in Stockholm were quite variable. Five different studies (#3598, #3599, 3600, #3602, #3606) showed that anywhere between 14% and 36% of patients required transfusions because of anemia, a rather wide variation. As many as 48% of patients had "major hematologic adverse reactions" (anemia or lowered white cell count). In one study (#3600), 70% of patients were able to remain on full-dose AZT for 6 months, but in another study (#3609), only 12% of patients were able to remain on full dose after 6 months. Reduced dose AZT The problem with toxicity with AZT is not new, and many solutions have been proposed. One of these is to use a reduced dose of AZT at the outset, instead of waiting for toxicity to develop. A large, NIH- sponsored trial comparing half-dose to full-dose AZT will not yield any conclusions for at least another year; this delay was one of the big disappointments of the conference. Approximately one year into the study, an indepen- dent safety monitoring board (who know who is receiving half-dose and who is receiving full-dose AZT) has noted no significant differences between these two groups, but researchers are quick to add that an additional year of study is necessary to draw sta- tistically firm conclusions. Is half-dose AZT as effective as full-dose? Unfortunately, we still don't know. In the meantime, many PWAs who are forced to take half-dose AZT because of toxicity ask the same question: "Should I be taking some other antiviral (e.g., Dextran sulfate) in addition to AZT?" This is another question with no clear answer -- we're not sure Dextran sulfate is an effective antiviral in people, let alone what is the most effective dose. The AZT/Acyclovir combination Another potential solution to the AZT toxicity problem is to combine it with high-dose Acyclovir (Zovirax). This combination seems to be particularly good in the test tube, and may mean that lower doses of AZT in combination with Acyclovir could be as effective as full-dose AZT. A NIH-sponsored study of this ques- tion has been underway for several months but, to everyone's disappointment, has yielded precious little data. In this study (#3137), 24 patients (all with ARC) were given either quarter- dose AZT (50 mg every 4 hours), half-dose AZT (100 mg every 4 hours), or full-dose AZT. This was combined with acyclovir (800 mg every 4 hours). Many subjects had not even been on the therapy for 12 weeks by the time of the Stockholm meeting. Obvi- ously, this is too small a group of patients and too short a study to draw conclusions about survival; however, the research- ers were able to demonstrate an antiviral effect even at the 50 mg dose of AZT and stated "The concomitant administration of Acy- clovir affords additive antiviral effect without a discernible change in toxicity." Surprisingly, other researchers (#3135) did not observe this antiviral effect, but stated (#3134) that the combination was well tolerated. Other studies (#3136, #3139) confirmed that the addition of Acyclovir does not change the metabolism or increase the toxicity of AZT. Treatment Issues has reported on the results of the one-year European trial of AZT (full-dose) plus Acyclovir (800 mg every 6 hours) in AIDS patients who have had prior opportunistic infec- tions. ((( Seligmann, M. Zidovudine, plus or minus Acyclovir in the treatment of AIDS patients post opportunistic infection. Presented at the IV International Conference on AIDS, Stockholm, 1988 ))) This is the only long-term, authoritative study of the combination to date. Researchers concluded that survival with the combination (91%) was improved as compared to AZT alone (72%). They also reported fewer episodes of herpes and CMV infections with the combination as opposed to AZT alone. This data call for serious consideration by anyone with full-blown AIDS on AZT of the addition of Acyclovir. A similar study in patients with ARC was presented. ((( Cooper D. The use of zidovudine in earlier symptomatic HIV infection (ARC). Presented at IV International Conference on AIDS, Stockholm, 1988 ))) 200 patients with ARC were random- ized to receive AZT alone, AZT plus acyclovir, or placebo for 24 weeks. Although it was clear that AZT alone was better than placebo (14% on placebo versus 0% on AZT progressed), "no fur- ther benefits from the addition of acyclovir were apparent dur- ing the initial study period, although the trial is now continu- ing without the placebo group to investigate this further." Thus, while there seemed to be a benefit of adding Acyclovir to AZT in the AIDS group, this did not hold up for the ARC group. This discrepancy underscores the fact that we simply don't know in what settings, if any, the AZT/Acyclovir combination is advan- tageous to AZT alone. The use of the AZT/Acyclovir combination for Kaposi's Sarcoma will be described in our next issue. AZT in early HIV infection Another possible solution to the toxicity problem with AZT is to give it to HIV-positive people who are asymptomatic and have a more intact immune system, as it is probable that these people will be much less likely to run into problems with the drug. Although there are large trials underway in this country to answer this question, it is much too early for any meaningful results. Only one small study was presented (#3634) on treatment of asymptomatic HIV-positive people with AZT, using an unusual dose of 500 mg every 12 hours -- essentially full- dose AZT but given only twice a day. The drug was well tolerated by this group. Researchers concluded that there was "an inhibitory effect on viral replication" and that AZT "appeared to slow down immunological deterioration", although they did not present hard data to support this conclusion. Thus, this study does not pro- vide a conclusive answer on this important issue. The AZT/ddC combination Treatment Issues (Vol. 2 no. 4) recently reported on ddC and the apparent benefit in combining it with AZT in patients who have had toxic reactions to AZT. Many patients are now on the combination for a year or more without serious toxicity, accord- ing to a paper (#3149) presented by American researchers. Uncon- firmed reports from the FDA have indicated that the AZT/ddC com- bination will soon be approved as a Treatment IND (an accelerated drug approval process for life- threatening illnesses). This would be a significant development for the growing numbers of patients who have been forced off AZT because they cannot tolerate it. Imuthiol/Antabuse There were two reports presented regarding Imuthiol. An 8- week study using intravenous Imuthiol (#3041) showed that patients with greater than 200 T4-cells had "stabilization of T4-cell count, less symptoms and regression of lymphadenopathy." Patients with less than 200 T4- cells did not do so well: all experienced disease progression. This is a small, short study and we should be cautious in making generalizations based on it. A somewhat larger (26 patients), longer (one year) study from the AIDS-Imuthiol French Study Group (#3055) found significant increases in T4-cells -- from an average of 385 to 483, whereas in the control (placebo) group, T4-cells declined significantly from 431 to 326. 30% of the control group declined clinically, while the treated patients all remained stable. While encourag- ing, we must recognize that these patients did not have advanced disease -- although 6 were described as having full-blown AIDS, the average T4-cell count is rather high, and none of the patients started out with less than 100 T4-cells. Still, if these figures are corroborated by the large study recently con- ducted in the United States, Imuthiol could be the first effec- tive immunomodulator drug for the treatment of AIDS and ARC. At a closed-door meeting in Stockholm, Institut Merieux, the developer of the drug, reportedly stated that the American study was "positive" (i.e., the drug was effective) and will confirm the French results. We'll see. A group of New York City researchers reported (#3042) the results of an informal monitor- ing project of the prescription drug Antabuse, which may be related to Imuthiol (see Treatment Issues, Vol. 2 no. 2). This study, which included AIDS and ARC patients, must be considered an "uncontrolled" study, as patients were on a variety of other agents besides Antabuse. The usual dose of Antabuse was 750 mg once a week or 500 mg twice a week. The mean T4-cell count in this group was 191 at the beginning of therapy and significantly increased to 259 at the end of the monitoring period. Overall, 58% of patients experienced a rise in T4-cells. Because of the multiple therapies used by most of the participants, this cannot be regarded as authoritative data, but suggests that Antabuse or a combination of drugs including Antabuse may be beneficial in AIDS. Unfortunately, no controlled study of the drug is planned. The researchers confirmed our prior report that "20% of the patients had abdominal cramps and/or diarrhea on the days of [Antabuse] intake." Aerosol Pentamidine Prophylaxis Perhaps the most exciting news to emerge from Stockholm is the tacit recognition that aerosolized Pentamidine has become a standard preventive treatment for PCP. An informal survey con- ducted in a conference room filled with roughly 200 doctors reflected that about two thirds of those present are routinely prescribing aerosolized Pentamidine as a prophylactic measure against this pneumonia, still the most frequently seen oppor- tunistic infection in PWAs. The chief advantage of aerosol administration of the drug as opposed to to intravenous ("IV") or intramuscular ("IM") injections is a significant decrease in tox- icity. When the aerosol mist is delivered directly to the lungs, it is much more effective against the pneumocystis organism, and spares the internal organs (kidneys, liver) that can be affected by IV or IM injections. While IV or IM Pentamidine is licensed by the FDA for treat- ment of diagnosed PCP, aerosol administration for treatment or prevention is still considered experimental. However, the drug is readily available, and patients should be able to locate a doctor willing to supervise a regimen of aerosolized Pentamidine. A number of large Phase II and Phase III studies are well under- way in the U. S., and preliminary results look very promising. Considering the good quality and amount of data on the safety and efficacy of aerosolized Pentamidine, licensing of this adminis- tration technique by the FDA seems imminent. Given the tremen- dous amount of data presented on aerosolized Pentamidine in Stockholm, it is impossible to review it all here. What follows is a summary of the most noteworthy results reported at the conference. Most of the references that follow list numbers of abstracts presented at the International Conference, rather than the full footnote form usually employed. The largest trial to date in the U. S. is being conducted at San Francisco General Hospital (#7166). A total of 438 patients has been randomized to three treatment doses: 30 mg biweekly (every other week), 150 mg biweekly and 300 mg monthly. During an average of 3.1 months treatment, only 12 cases of PCP occurred. These cases were fairly evenly distributed among the three dosage levels, lending credence to the hypothesis that a lower dose may be as effective in preventing PCP, when admin- istered by a nebulizer with an appropriately small droplet size. This possibility is certainly interesting from a financial per- spective. Also, this study showed smaller percentages of patients suffering minor adverse reactions such as cough and wheezing at the lowest dose. It is becoming more common for doc- tors to administer a bronchodilating aerosol to patients who experience coughing fits during treatment. Patients experiencing such difficulty should be aware of this potential relief. At Century City Hospital, another large Phase II trial (#7168) has yielded impressive results over 8 months of prophy- lactic treatment. 150 patients received 60 mg of aerosolized Pentamidine weekly for one month, then took the same dose biweekly. Only one case of PCP was reported in Stockholm, but the number of confirmed cases has since risen to three. A recurrence rate of only 3% is extremely promising. This study is increasing the dose to 300 mg monthly because this group feels that the higher dose is as effective as the lower one, a hypothesis that has not yet been substantiated. Nebulizers The common denominator for these two studies, which examined a variety of doses, is the nebulizer used. The Respirgard II (Marquest) creates a mist of particles which have a mean size of 1.42 microns. This size falls within what is considered the optimal range for delivery to the alveolar sacs in the lungs, the site where pneumocystis grows. On a related note, one study sug- gested that more efficient delivery of the drug may be achieved if the patient takes his treatment while lying down (#7167). Two smaller studies yielded less impressive results. At least one of these studies used a nebulizer that delivers larger particles. The LA County Medical Center and UCLA (#7170) coordi- nated a study of 29 evaluable patients who received roughly 140 mg of Pentamidine biweekly for an average of 26 weeks. Four patients developed "mild" cases of PCP, a rate of 13.7%. The abstract noted only that a "compressed air nebulizer" was used, and that the study was switching to a nebulizer that delivers particles in the 2 micron range. The same two institutions coor- dinated another, slightly larger study (#7171). Fifty-six patients were started on 60 mg biweekly. After an average of 70 days treatment at this dose, patients were switched to 150 mg biweekly, due to a high recurrence rate (24%). This rate declined to 6% after an average treatment time of 147 days. Patients used a hand held nebulizer, but the abstract did not report mean particle size. Investigators conclude that the higher dose offers greater protection, a finding that conflicts with the larger and longer study at San Francisco General Hospital. Finally, another study conducted in New York, at the Memorial Sloane-Kettering Cancer Center yielded encouraging data from a pool of 162 patients observed over an average of 7.1 months (#7169). Patients were administered 60 mg of Pentamidine weekly for one month followed by the same dose biweekly. Four "mild" cases of PCP occurred (approx. 2.4%). This recurrence rate was approximately 10 times smaller than that seen in "an earlier trial using the same dose and a less efficient nebulizer." The study employed an ultrasonic nebulizer ("Fisoneb") delivering average particles of 4.7 microns. According to lead investigator Edward Bernard, the appropriate breathing method will further shrink particles to an average of 2.4 microns. The study is ongoing and now has three arms: patients with a history of 2 or more cases of PCP are receiving 60 mg weekly, and all other par- ticipants are randomized to 60 or 120 mg biweekly. The recurrence rate remains below 3% a year. Dr. Bernard also claimed that the Fisoneb is much more efficient than the Respir- gard. Data from radio aerosol deposition studies show that the Fisoneb delivers the same amount of drug with a 60 mg dose as the Respirgard does with a 300 mg dose. Considering the difficulties patients have had seeking reimbursement for Pentamidine, this difference has serious financial implications. Dr. Bernard also believes that the optimal dose of aerosolized Pentamidine will vary from patient to patient, depending on the status of each individual's immune system. Treatment Issues has been informed that a new, more effi- cient nebulizer will soon be available -- probably this fall. The Porto-Sonic is a compact nebulizer manufactured by DeVilbiss Co. Its most touted marketing feature is an attached recharge- able battery that allows patients to use the machine anywhere. The battery will run the nebulizer for about one hour, limiting the number of treatments one can safely expect when relying on the battery to one. An adapter will also allow the nebulizer to be run off a car cigarette lighter. Of more practical concern, this nebulizer delivers particles in the average size of 1.8 microns. It also appears to be much more efficient than nebuliz- ers now available. The Porto- Sonic, according to company claims, delivers approximately 25% of the drug to the lungs. It should be emphasized that information is not yet available con- cerning what portion of this 25% actually lodges in the alveolar sacs, the area where Pentamidine is most useful. Also, patients should be aware that too much drug could cause adverse reactions. The majority of nebulizers currently used deliver about 6% of the drug to the alveoli. This "top shelf" machine will also be more expensive than most nebulizers on the market. According to Kath- leen Bradley of Foster Medical Corp., a home health care company, Medicaid has indicated that they may reimburse for this machine if the patient's doctor can justify the need for a more efficient piece of equipment. There is no policy yet concerning the Porto-Sonic, and it remains to be seen if patients will be granted reimbursement. Summary As aerosolized Pentamidine becomes more and more routine as prophylactic therapy, we can make some cautious generalizations based on the significant number of studies that have examined this drug. First, particle size is a crucial parameter. Also, the San Francisco General Hospital study suggests little or no difference in efficacy between doses ranging from 60 mg a month to 300 mg a month. These findings are encouraging in terms of lower toxicity and cheaper treatment, but it is still too early to recommend a particular dose. In Brief Recent reports from researchers and physicians using the drug DHPG (Ganciclovir) indicated that Syntex, the manufacturer of the drug, may stop making the drug available on Compassionate Use basis. The FDA has refused approval of the drug but has allowed Syntex to distribute it compassionately pending the accu- mulation of more data on the safety and efficacy of the drug, which is the only available therapy for serious cytomegalovirus (CMV) infections. Although Syntex admits there will be changes in the mechanisms of distribution of the drug, they have issued the following statement: "We are carefully evaluating the alter- natives and will be sure that we have adequately provided for the continued treatment of patients who need ganciclovir when we make a final decision." We will stay abreast of developments on this front. The Omega Institute for Holistic Studies is conducting a training and retreat for AIDS caregivers, to be held on September 8-11, 1988 in Rhinebeck, NY. The objectives include Retreat -- relaxation and contemplation, Medical Training -- both conven- tional and holistic, and Networking -- linking up resources and exposure to others in the field. For more information on this important conference, call (800) 862-8890. A new book called A Gay Men's Health Manual for the Age of AIDS: Strategies for Survival has recently been published. Writ- ten by gay people for gay people in a realistic, caring and understanding tone, the book presents a balanced, step-by-step approach to the goal of an overall health maintenance. Single copies are $10.95 (plus $1.50 shipping). Write: St. Martin's Press, Inc., 175 Fifth Avenue, NY, NY 10010. New Studies The Mount Sinai Medical Center is conducting a study of two topical medications (hydrocortisone vs. ketoconazole) in AIDS/ARC patients with seborrheic dermatitis (a common skin condition). Preliminary reports ((( Skinner R et al. Double-blind treatment of seborrheic dermatitis with 2% ketoconazole cream. J Am Acad Dermatol 12: 852, 1985 ))) indicate that the anti-fungal ketocona- zole may be effective in this condition, which may, in fact, be caused by a fungus. Interested physicians may contact Dr. Daniel Groisser at (212) 517-4630 or (212) 996-6910. Triton Biosciences, manufacturer of Betaseron (a- interferon), is launching a large trial of half-dose AZT plus Betaseron in the treatment of AIDS and advanced ARC. All patients will receive half-dose AZT (100 mg every 4 hours); one- third will receive 9 million units Betaseron daily (by injec- tion), one-third will receive 45 million units daily, and one- third a placebo injection. Eligible patients are anyone who can- not tolerate full-dose AZT but who can tolerate half-dose AZT. PCP prophylaxis is permitted. The hope of this phase III trial is to inhibit HIV replication and to prevent opportunistic infec- tions to a greater degree than half-dose AZT alone. The large, NIH-sponsored study of half-dose AZT won't yield any conclusions for at least a year. As more and more patients are reduced to half-dose AZT because of toxicity, the possibility of adding other drugs that may be synergistic with AZT seems increasingly attractive. Betaseron is one such drug which has shown to be synergistic with AZT in the test tube. ((( Carron WC et al. Anti-HIV activity of a-interferon in combination with AZT. IV International Conference on AIDS, Stockholm, 1988, #3633 ))) Previous studies of higher doses of a-interferon for the treatment of KS were somewhat disappointing, having a 30% response rate; ((( Miles SA et al. Betaseron interferon has in vivo activity against HIV and AIDS related KS. IV International Conference on AIDS, Stockholm, 1988, #3515 ))); however, a sig- nificant anti-HIV effect was noted as evidenced by reduction in p24 levels (a viral protein) and ability to culture HIV. As for side effects, tolerance is expected to be very good: a-interfe- ron is generally better tolerated than alpha-interferon. All things considered, this study deserves serious consideration for anyone who is on half-dose AZT. The following physicians will be enrolling patients: NY - Mt. Sinai Medical Center: Dr. Henry Sacks, (212) 241-7856. NY - NYU Medical Center: Dr. Ron Blum, (212) 340-7227. NY - Beth Israel Medical Center: Dr. Donna Mildvan, (212) 420-4005. NY - St. Vincent's Hospital: Dr. David Kaufman, (212) 620-0144. NY - Memorial Sloan-Kettering Cancer Center: Dr. Susan Krown, (212) 794-7426. CA - University of California at San Francisco: Dr. Paul Volberding, (415) 821-5531. CA - University of California at Los Angeles: Dr. Ronald Mitsuyasu, (213) 206-8359. CA - University of Southern California: Dr. Alexandra Levine, (213) 226-7504. CA - Cedars Sinai Medical Center: Dr. David Ho, (213) 855-3896. CA - Santa Clara Valley Medical Center: Dr. Stanley Deresinski (408) 299-5587. DC - George Washington University: Dr. Richard Schulof, (202) 994-3693. IL - Northwestern University Medical School: Dr. Jamie von Roenn, (312) 908-5284. MA - Boston University Medical Center: Dr. William Hauser, (617) 638-7909. TX - Baylor University: Dr. Steve Greenberg, (713) 799-4775. TX - University of Texas at Galveston: Dr. Rich Pollard, (409) 761-2427. In February, Treatment Issues announced a new study of the antidepressant medicine Tofranil in patients with HIV infection exhibiting signs of depression. Half of patients receive the drug and half placebo, but non-responders to placebo will be offered a 6-week course of the drug. Preliminary reports from the investigators are encouraging, and they are seeking additional subjects. Call Donna Manning, M. D. at The New York Hospital, (212) 874-2630. Treatment Issues recently announced a study of AZT in sero- positives with greater than 500 T-cells. There has been a change in this study, which has now been reopened to those asymptomatics with fewer than 500 T-cells. Patients will receive either 1500 mg daily of AZT, 500 mg of AZT, or placebo. This study is essential in determining whether or not asymptomatic seropositives should be on AZT, and seems completely ethical, considering that these individuals have a good prognosis over the time course of the study. Those interested in participating may call Delia Brown, RN or Cynthia Vassallo, RN at (212) 794-7163. Other Resources American Foundation for AIDS Research (AmFAR) has updated their catalog of trials involving experimental drugs. The "AIDS/HIV Experimental Treatment Directory" also includes several glos- saries and information about the federal clinical trials efforts and licensing of drugs. Write to AMFAR at 40 West 57th St., New York, N. Y. 10019, or call (212) 333-3118. "AIDS Treatment News" is a short, biweekly report which chroni- cles current developments in experimental and alternative treat- ments and deals with public policy issues. Contact John S. James at P. O. Box 411256, San Francisco,CA 94141 or call (415) 282- 0110. "PWA Coalition Newsline", published "by and for people with AIDS and AIDS Related Conditions," is a grass-roots news magazine that appears monthly. The publication reports news developments deal- ing with the health crisis as well as alternative treatments. Editorials and literary contributions add another interesting dimension to this excellent source of information. Write PWA Coalition Inc., 263A West 19th St., Room 125, New York, N. Y. 10011, or call (212) 627-1810. Ask about their other publication, "Surviving and Thriving with AIDS". "ATIN" (AIDS Targeted Information Newsletter) performs a monthly search of hundreds of medical journals worldwide. Defin- itely aimed at doctors and researchers, it is the best ongoing literature search available. It has an impressive cast of editors who comment on the significance of the studies cited. Published by Williams & Wilkins, P. O. Box 23291, Baltimore, MD 21203 or phone 1-800-638-6423. Project Inform publishes an excellent newsletter called "PI Per- spective" which deals with experimental treatments and focuses special attention on drug regulatory issues and public policy. Another valuable resource is their up-to-date drug hotline. Call them at 1-800-822-7422. Body Positive is a new organization established by and for HIV- antibody-positive people to exchange information, advocate research, fight discrimination, andp rovide mutual emotional sup- port. They publish a monthly newsletter called "The Body Posi- tive." Write to: 263A West 19th Street, New York, NY 10011 or call 212-633-1782. "Healing AIDS" is a monthly magazine which focuses on holostic approaches to AIDS and ARC including diet and nutrition, relaxa- tion and visualization techniques, and stress reduction. It re- gularly lists other resources. Subscriptions are $10/year for peo- ple with AIDS/ARC/low income, and $15 for others. Write: 3835 20th Street, San Francisco, CA 94114 or phone: (415) 821-7646. The AIDS Health Project at the University of California San Fran- cisco publishs a monthly newsletter called "Focus" written "to place data and medical reports in a context that is meaningful and useful to its readers." It provides easy-to-understand prac- tical information on AIDS research. Contact UCSF AIDS Health Project, Box 0884 San Franciso CA 94143 or phone (415) 476-6430. Treatment Issues is GMHC's newsletter devoted to providing reli- able information on experimental AIDS therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be done under a physician's care. Treatment Issues is published ten times yearly. Copyright 1988 Gay Men's Health Crisis, Inc. All rights reserved. Non- commercial reproduction is encouraged. Subscription lists are kept confidential. Editor: Barry Gingell, M. D. Managing Editor: Kevin Armington GMHC, Department of Medical Information, 129 West 20th Street, New York, NY 10011. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display