Original Article
Aerosolized Pentamidine for Prophylaxis against Pneumocystis carinii Pneumonia — The San Francisco Community Prophylaxis Trial
N Engl J Med 1990; 323:769-775September 20, 1990
- Abstract
- Abstract
Background and Methods.
Pneumocystis carinii pneumonia (PCP) is the most frequent life-threatening opportunistic infection associated with human immunodeficiency virus (HIV) infection. To assess the possible value of aerosolized-pentamidine prophylaxis in different doses, a controlled clinical trial was begun in 1987 with 408 subjects at 12 treatment centers. The participants were randomly assigned to receive 30 mg of pentamidine every two weeks, 150 mg every two weeks, or 300 mg every four weeks.
Results.
Eighteen months after randomization, the subjects in the 300-mg arm had had 8 confirmed episodes of PCP while receiving treatment, as compared with 22 in the 30-mg arm (P = 0.0008). The 150-mg arm had intermediate results but ones not significantly different from those of the 300-mg arm. Participants with previous episodes of PCP and CD4-cell counts less than 200 per cubic millimeter were at the highest risk for PCP.
Conclusions.
Aerosolized pentamidine was effective for prophylaxis against PCP in patients infected with HIV, according to the dose and schedule of administration. It and zidovudine were well tolerated together and had independent prophylactic benefits. (N Engl J Med 1990; 323: 769–75.)
Article Activity
- Article
Pneumocystis carinii pneumonia (PCP) is the most frequent life-threatening opportunistic infection leading to the diagnosis of the acquired immunodeficiency syndrome (AIDS), having affected at least 70,000 persons in the United States since 1981.1 In patients with human immunodeficiency virus (HIV) infection, PCP is the most frequent cause of death.2 In other immunosuppressed patients and patients with AIDS who have Kaposi's sarcoma, prophylaxis with trimethoprim–sulfamethoxazole has been successful in preventing PCP.3 4 5
In HIV-infected patients, adverse effects of trimethoprim–sulfamethoxazole, parenteral pentamidine, and pyrimethamine—sulfadoxine have limited the long-term administration of these drugs.6 In contrast, aerosolized pentamidine can be delivered directly to the alveolar space, where P. carinii infection is usually concentrated.7 It has an unusually long tissue half-life in the lung, with low systemic drug levels and toxicity.8 9 10 Like other prophylactic agents, aerosolized pentamidine is effective in increased dosages for treatment of acute PCP.11 12 13 14 15
When this trial was initiated, aerosolized-pentamidine therapy was becoming a community standard of practice as a result of encouraging early reports from uncontrolled trials. A controlled trial of adequate size and duration was needed to assess the efficacy and safety of this treatment.
Methods
Study Population
The study involved a prospective, randomized, unblinded comparison of three dosages of aerosolized pentamidine over an 18-month period. Randomization was blocked in time with random block sizes and stratified into three groups, according to the participants' history of HIV complications. The three strata included participants with at least one previous episode of PCP (the previous-PCP stratum), those with Kaposi's sarcoma who had never had PCP (the Kaposi's sarcoma stratum), and those with AIDS or AIDS-related complex but no history of PCP or Kaposi's sarcoma (the other-conditions stratum). Participants were excluded if they had had severe asthma, an anaphylactic reaction to pentamidine, or previous prophylaxis with aerosolized pentamidine or if they were currently (within the previous two weeks) using agents wilh known or likely efficacy against P. carinii.
Participants were enrolled at 12 treatment centers in the San Francisco Bay area. Health care providers al these centers enrolled participants by contacting the data center, which provided randomization numbers and assigned one of the following treatment doses: 30 mg of aerosolized pentamidine every two weeks, 150 mg every two weeks, or 300 mg every four weeks. Each stratum had a separate set of sealed cards, with treatments assigned in random blocks of three and six. Informed consent for treatment and follow-up was obtained at the first treatment visit.
Treatment Method
Pentamidine isethionate was reconstituted in 6 ml of sterile water and administered for 35 to 40 minutes in a Respirgard II nebulizer (Marquest, Englewood, Colo.), either at a flow rate of 5 to 7 liters per minute from a pressure-compensated flowmeter attached to a 344.5-kPa (50-psi) source of dry gas or at a pressure of 151.6 to 172.2 kPa (22 to 25 psi) from a Bunn BA 400 air compressor (John Bunn, Tonawanda, N.Y.).8 Each treatment was supervised by a respiratory therapist, who noted any immediate adverse effects and administered a bronchodilator if needed for severe coughing or bronchospasm.
Each participant was followed from the first treatment, on or about July 1, 1987, until death or December 31, 1988. Six of 408 participants were lost to follow-up but were not considered ineligible for this reason. Participants were questioned at base line and at each visit about concomitant medications, intercurrent illnesses, and symptoms. Status was determined on the basis of information from the participants, their physicians, hospital records, microbiology departments, and county death records.
Definition of Terms
PCP episodes were considered to be occurrences of pneumonitis that were clinically consistent with acute PCP, including those in which the participants may or may not have had histologic confirmation but either responded to autipneinnocystis therapy or died without confirmation of another pulmonary diagnosis. Confirmed PCP episodes were defined as episodes for which there was histologic confirmation of the diagnosis from samples of induced sputum or specimens obtained by bronchoscopy or open-lung biopsy. Cases of pneumonitis in which bronchoscopy was negative were considered not to involve PCP. Deaths due to PCP were defined as deaths that occurred during treatment for acute PCP.
Participants were considered to be "eligible" until 60 days after they had discontinued use of the study drug, unless they were found to be taking a prohibited medication at the time of randomization (17 patients), had received previous prophylaxis with aerosolized pentamidine (10), were HIV-negative (1), or either had a PCP episode (12) or died within the first 28 days of the study (2). Patients in whom PCP developed within the first 28 days probably already had the infection at enrollment, For this reason, they were eliminated from all analyses of eligible participants. Six were randomly assigned to the 30-mg dose, four to the 150-mg dose, and two to the 300-mg dose of aerosolized pentamidine. Eight were in the previous-PCP stratum, one in the Kaposi's sarcoma stratum, and three in the other-conditions stratum.
Data Analysis
The intention-to-treat analysis included all 408 participants who took the study drug and all end points, whether these occurred while the participants were taking the study medication or not. Although this analysis estimates efficacy conservatively, it protects against possible bias created by the exclusion of ineligible participants and differential withdrawal from the study drug. All the analyses of mortality used the intention-to-treat rule.
Within the total number of participants, data on a subgroup of 366 eligible participants were analyzed. For this analysis, episodes of PCP that occurred more than 60 days after the last treatment were not counted as having occurred during the study and were censored. The analysis of confirmed episodes of PCP included only those for which a histologic diagnosis was secured.
The hypothesis was tested in each pair of doses with a Bonferroni adjustment of the P value, yielding three planned comparisons (30 mg vs. 150 mg, 30 mg vs. 300 mg, and 150 mg vs. 300 mg). Two interim analyses and a final analysis were performed with the method of O'Brien and Fleming, yielding P values of 0.0006, 0.015, and 0.047, respectively.16 Thus, the Bonferroni-adjusted P value for the significance of the final comparisons between any pair of doses was 0.016. Measures of significance are reported as unadjusted P values.
Differences between doses were tested with the log-rank statistic of the Kaplan–Meier product-limit estimates with use of the Proc Lifetest of SAS. In addition, the Cox proportional-hazards regression model was performed with BMDP (L2) to estimate the effects of covariates.
Results
Study Population
Four hundred forty-one persons were randomized. Thirty-three of these were never treated with the study drug (10 in the 30-mg arm, 13 in the 150-mg arm, and 10 in the 300-mg arm) and were not included in any of the analyses. These participants withdrew from the study before their first visit to a treatment center and before consenting to follow-up. Of the 408 study participants treated, 237 were in the previous-PCP stratum, 55 in the Kaposi's sarcoma stratum, and 116 in the other-conditions stratum (Table 1Table 1
Characteristics of the Participants at Entry into the Study, According to the Randomized Treatment Dose.).All but three participants were men. Their ages ranged from 20 to 62 years (mean, 37.7). Their HIV-related diagnoses included disseminated infection with Mycobacterium avium-intrellulare, cryptococcal meningitis, central nervous system toxoplasmosis, lymphadenopathy, oral candidiasis, hairy leukoplakia, and herpesvirus infections. These conditions were evenly distributed among the treatment groups (Table 1). In addition to the 55 participants in the Kaposi's sarcoma stratum, 52 participants in the previous-PCP stratum had Kaposi's sarcoma. The participants with a history of PCP started the study an average of 135 days after the most recent episode (range, 13 to 1011; median, 74). This interval did not differ significantly among the randomized groups.
Although base-line CD4-cell counts were not recorded as part of the protocol, a subsequent review of medical records revealed CD4 counts obtained within one month of entry into the study in 128 participants (35 in the Kaposi's sarcoma stratum and 93 in the other-conditions stratum). The CD4-cell counts for these participants ranged from 8 to 676 per cubic millimeter (mean, 160.8; median, 128) and did not differ significantly among randomized groups.
The most frequent medication taken concomitantly was zidovudine, taken by 214 participants (52 percent) at the start of the study. Another 81 participants (20 percent) started zidovudine therapy during the study. Other medications frequently taken concomitantly or previously were acyclovir (94 participants, 23 percent), clotrimazole (59 participants, 15 percent) and ketoconazole (15 participants, 4 percent). Previous use of drugs for prophylaxis was reported by 61 participants (15 percent); 29 participants (17 receiving concomitant prophylaxis and 10 who had previously received aerosolized pentamidine) were disqualified from analysis.
Study Outcome
The study began July 1, 1987, and ended December 31, 1988. One hundred six participants (26 percent) completed the study without reaching a study end point. The 30-mg dosage arm had the fewest participants completing the study, primarily because there were more PCP events in this arm (Table 2Table 2
Participants' Outcomes at the Conclusion ot the Study.).One hundred one episodes of PCP were documented during the study, including 26 that occurred more than 60 days after the discontinuation of treatment. Seventy-eight occurred in the previous-PCP stratum, 8 in the Kaposi's sarcoma stratum, and 15 in the other-conditions stratum. Twenty-five episodes were not histologically confirmed. Sixty-two of the 101 episodes occurred while the participants were involved in the Study (i.e., more than 28 days after the start of treatment and fewer than 60 days after the last administration of aerosolized pentamidine).
One hundred sixty participants died; for 43 of these, death was the first study end point. Nineteen deaths were due to PCP. Sixteen were associated with a first episode of PCP after the start of the study, and three with second or third episodes.
One hundred eighty-six participants were withdrawn from the study bin followed to the end of the trial. Six were lost to follow-up. The most common reasons for discontinuation were noncompliance, other protocol violations, dose increase, and dose decrease (Table 2). Noncompliance was defined as a treatment gap of more than two months. The duration of aerosolized-pentamidine treatment for all participants ranged from 1 to 536 days (median, 212).
Prevention of PCP
The 300-mg dosage arm had the fewest PCP episodes, whether analyzed according to the intentionto-treat or the eligible-participant rule (Table 3Table 3
PCP Events, According to Dose of Aerosolized Pentamidine and Eligibility Status.). Kaplan–Meier plots of the proportion of participants in the study remaining free of PCP while taking the study drug showed a widening difference in effectiveness when the 30-mg dosage arm was compared wilh the 300-mg arm over time (Fig. 1Figure 1
Percentages of 366 Eligible Participants Who Remained Free of Confirmed PCP during Prophylaxis with Aerosolized Pentamidine (Kaplan–Meier Estimates). and 2Figure 2
Percentages of 208 Eligible Participants with Previous Episodes of PCP Who Remained Free of Confirmed PCP during Prophylaxis with Aerosolized Pentamidine (Kaplan–Meier Estimates).). The comparison of the 30-mg arm with the 300-mg arm by the log-rank statistic showed a statistically significant difference at all levels of the analysis (Table 3).The Cox proportional-hazards regression model estimated the dose response for aerosolized pentamidine with control for base-line covariates (Table 4Table 4
Estimates of the Relative Hazard of PCP, According to Cox Regression Analysis.*). These included study stratum, treatment center, zidovudine use, and time since previous PCP. The 300-mg group had a significantly lower hazard of PCP according to either intention-to-treat or eligible-participant analysis. The same results were obtained in the previous-PCP stratum alone. The 150-mg dose was consistently less effective than the 300-mg dose when both were compared with the 30-mg dose, although the difference was never statistically significant.Zidovudine use independently reduced the risk of PCP twofold in the Cox model. Increased time since the occurrence of previous PCP also predicted an increased risk independently in the Cox model. Participants starting therapy within three months of an episode had less than half the hazard of PCP of those starting later, suggesting improved efficacy with earlier initiation of prophylaxis. PCP relapses occurred after a median of 240 days in participants starting prophylaxis within three months, as compared with 143 days in those starting later after the previous episode.
A CD4 count below 200 cells per cubic millimeter was associated with a relative risk of PCP of 2.6 (95 percent confidence interval, 0.62 to 11.2) in participants without previous PCP (Fig. 3Figure 3
Primary Prophylaxis: Relation between Pretreatment CD4 Count and Development of PCP during the Study.). PCP developed in 2 of the 39 participants with initial CD4 counts above 200 per cubic millimeter (5.1 percent), as compared with 12 of the 89 participants who had initial CD4 counts under 200 per cubic millimeter (13 percent).Mortality
Mortality from all causes did not differ significantly among the three treatment arms (Fig. 4Figure 4
Survival among the 408 Participants (Kaplan–Meier Estimates).). There was little power to detect a dose response for mortality from PCP, since PCP was the cause of only 11.9 percent of all deaths (19 of 160). Forty-one percent of all deaths were caused by opportunistic infections with organisms other than P. carinii. Mortality was higher in the previous-PCP (53 percent) stratum than in the Kaposi's sarcoma (36 percent) or other-conditions (13 percent) stratum. The participants who had never taken zidovudine had a significantly higher mortality (67 percent) than those who had taken this drug (28 percent). The case fatality rate for the first acute episode of PCP after randomization was 15.8 percent (16 of 101 episodes of PCP). There were no significant differences among dosage arms. At autopsy 11 months after stopping the study and 7 months after his last dose of aerosolized pentamidine (received off study), one participant was found to have calcified granulomas in the liver and spleen that contained P. carinii. He had died of a wasting syndrome, and the contribution of the extrapulmonary pneumocystis was not clear.Adverse Experiences
Respiratory therapists reported that serious coughing occurred in 36 percent of participants and wheezing in 11 percent. The previous-PCP stratum reported a significantly higher incidence of cough with the administration of aerosolized pentamidine (43 percent). Wheezing occurred in significantly more participants in the 150-mg and 300-mg dosage arms but did not differ in incidence across strata. Although it occurred commonly, cough interrupted only 0.5 percent of all treatments and required the discontinuation of only 0.3 percent (Table 5Table 5
Incidence of Adverse Respiratory Reactions in the Study Participants.). Fourteen percent of the participants used bronchodilators at least once; the use of these agents was more common in the 150-mg and 300-mg dosage arms.Twenty-three participants (5.6 percent) discontinued aerosolized-pentamidine treatment because of adverse experiences. In nine (2.2 percent), the adverse experiences were directly associated with treatment. Bronchospasm and cough developed in four, and the following conditions developed in one patient each: dizziness and lightheadedness; upper respiratory symptoms and lip numbness; diaphoresis, unsteadiness, and nausea; gagging; and a rash that recurred on rechallenge. One participant stopped the study medication after a single treatment because of interstitial pneumonitis, the cause of which was unknown, but the condition was noted to have been present before the start of aerosolized-pentamidine therapy. Ten participants withdrew because of concurrent illnesses or infections related to HIV, and four withdrew after pneumothoraxes.
Pneumothorax occurred in 21 participants treated with aerosolized pentamidine. (Two occurred more than four months after the last treatment.) Eight were spontaneous, four caused by invasive procedures, six associated with acute PCP, and three with bacterial pneumonia. There was no difference in frequency of occurrence among treatment arms (Table 5). No pneumothorax occurred during a treatment. Only two of the participants with pneumothorax had no previous or concomitant PCP; one pneumothorax was precipitated by a transbronchial biopsy.
Discussion
PCP is the leading cause of death from opportunistic infections in patients with HIV infection. Sixty-three percent of patients with AIDS have PCP as their index diagnosis, and over 80 percent of all patients with AIDS have at least one episode.2 Early diagnosis and treatment lower the acute case fatality rate, but death still occurs in 15 to 30 percent of episodes. Recovery from any single episode of PCP does not confer immunity from another bout. By the time second episodes occur, many patients have become intolerant of the short list of drugs with proved efficacy against acute PCP. Pulmonary parenchymal fibrosis is common after PCP, and there is progressive damage to pulmonary function with successive infections. Therefore, successful prophylaxis, primary and secondary, is critical to the prolongation of survival in patients with AIDS. Zidovudine prolongs life after PCP17 but does not prevent subsequent episodes.18
Trimethoprim–sulfamethoxazole is well tolerated and prevents PCP in children with leukemia.3 , 4 Although primary prophylaxis with trimethoprim–sulfamethoxazole and leucovorin was successful in patients with Kaposi's sarcoma as compared with no treatment,5 adverse reactions occurred in 50 percent of participants and necessitated the discontinuation of treatment in 13 percent. With previous exposure, patients with AIDS are often intolerant of trimethoprim–sulfamethoxazole, and one placebo-controlled, randomized, double-blind trial was stopped because of the high incidence of such intolerance.19 Other medications likely to be effective for PCP prophylaxis include dapsone, pyrimethamine—sulfadoxine (Fansidar), and parenteral pentamidine20 21 22; these are now undergoing evaluation.
The choice of a dose–response design to study prophylaxis with aerosolized pentamidine was suggested by reference to a consecutive series of patients treated with 30 mg every two weeks23 as compared with historical controls.24 Although there were less than half the expected number of PCP episodes, there were also enough "breakthrough" episodes to warrant a study to determine both optimal treatment dosage and interval.
The administration of aerosolized pentamidine in three dosage arms (30 mg every two weeks, 150 mg every two weeks, and 300 mg every four weeks) was compared by the log-rank statistic of the Kaplan–Meier curves and with Cox proportional-hazards regression models. In the Kaplan–Meier analyses of the time to the occurrence of PCP, 300 mg given every four weeks was consistently superior to 30 mg given every two weeks. The 150-mg arm was superior to the 30-mg arm, but less so than the 300-mg arm. The Cox relative hazard of 300 mg as compared with 30 mg for PCP events in eligible participants was 0.26; for 150 mg as compared with 30 mg, the relative hazard was 0.58.
Patients wilh a previous episode of PCP (those receiving secondary prophylaxis) had the highest risk of PCP. The superiority of the 300-mg dose was observed in this stratum alone. A significant dose response was not found for primary prophylaxis in the two other strata, most likely because the small number of events did not provide adequate power. The Cox model for intention to treat estimated the risk of PCP in the primary-prophylaxis strata at 0.26 to 0.33, as compared with the risk in the secondary-prophylaxis stratum. Both epidemiologic studies and our results showed an increased risk for participants receiving primary prophylaxis who have CD4 counts below 200 cells per cubic millimeter.18
Although the incidence of pulmonary side effects was high, their severity was low. Only 2.2 percent of the participants withdrew from the study regimen because of respiratory side effects attributed to aerosolized pentamidine. The most frequent adverse experience was cough, reported by 36 percent of the participants at some time during the study. Cough resulted in study discontinuation in only 1 percent, and it required the interruption of treatment in only 0.5 percent of all participants. There were eight participants (2.0 percent) with pneumothoraxes of unknown cause. Although a relation of these events to treatment with aerosolized pentamidine cannot be excluded, they did not occur during treatment, nor was their incidence higher among the participants in the higher-dosage arms.
Despite the low rates of adverse reactions requiring discontinuation, this study did not eliminate the possibility of long-term systemic or pulmonary toxicity of aerosolized pentamidine. Extrapulmonary pneumocystis, which may become more common with prophylactic therapy directed solely at the lungs, was found at autopsy in one participant.
For effective prophylaxis, a patient must be able to tolerate both the prophylactic agent and zidovudine. Many sulfa drugs have adverse hematologic effects that require frequent monitoring and dose reduction of the sulfa drug, the zidovudine, or both. Aerosolized pentamidine, with its low systemic absorption, avoids this problem. Aerosolized pentamidine and zidovudine were well tolerated together in this study. This finding confirms the observation of Girard et al.,25 who found benefit from combining aerosolized pentamidine and zidovudine.
Among the participants with a history of PCP, those who started prophylaxis more than three months after the last PCP episode had a relative hazard of 2.3 for a subsequent episode, as compared with those who started prophylaxis earlier. This suggests that patients should begin prophylaxis immediately after the completion of short-term therapy for PCP.
Aerosolized pentamidine is an effective method of prophylaxis for HIV-infected patients at high risk for PCP. Adverse experiences due to the drug are fewer and less severe than those occurring with systemic regimens. Further prospective randomized trials are needed to determine whether higher doses provide more efficacy without additional adverse experiences. Trials comparing aerosolized pentamidine with systemic agents would clarify the relative safety and efficacy of the two routes of administration and the relation of aerosolized pentamidine to extrapulmonary pneumocystosis. The combination of prophylaxis and antiretroviral therapy may prove to prevent most episodes of PCP in patients with HIV infection.
*The San Francisco County Community Consortium included the following: Bruce Bartlow, M.D., Keith Barton, M.D., Eugene Belogorsky, M.D., Jeremy Berge, M.D., Robert Bolan, M.D., Jerry Bolduan, M.D., Mark Bresnik, M.D., Barbara Brodie, N.P., Carol Brosgart, M.D., James Campbell, M.D., Lisa Capaldini, M.D., Gary Carr, N.P., Richard Cazen, M.D., Michael Chase, M.D., Steve Chuck, M.D., Michael Clement, M.D., Marcus Conant, M.D., Molly Cooke, M.D., Mary Lou Cullinan, M.D., Richard Dolbec, M.D., David Drennan, M.D., W. Lawrence Drew, M.D., Toby Dyner, M.D., Milton Estes, M.D., Robert Fallat, M.D., Maureen Flaherty, M.D., Stephen Follansbce, M.D.,Cheri Forrester, M.D., David French, M.D., Harrison Gill, M.D., Robert Gorter, M.D., Sandra Hernandez, M.D., Walter Howard, P.A., Peter Jensen, M.D., Patrick Joseph, M.D., James Kahn, M.D., William Kapla, M.D., Walter Krampf, M.D., Marshall Kubota, M.D., Erick Kwok, M.D., William Lang, M.D., Alison LaVoy, M.D., Brad Lewis, M.D., Myles Lippe, M.D., Joseph Marzouk, M.D., Martin Mass, M.D., Michael McCune. M.D., Patrick McGraw, M.D., Steve Mehalko, M.D., Timothy Mess, M.D., John Mills, M.D., David
Minor, M.D., J.B. Molaghan, N.P., William Owen, M.D., Michael Pawlik, M.D., Roger Phelps, M.D., Lauren Poole, N.P., Thomas Schiller, M.D., Ivan Silverberg, M.D., Les Soloman, M.D., John Swartzberg, M.D., Jean-Luc Szpakowski, M.D., George Tardelli. M.D., Andrew Wagner, M.D., and Charles Williamson. M.D.
Treatment centers: Children's Hospital of San Francisco: Robert Dachille, R.R.T., Michael Erhard, R.R.T., Julie Sanford; Davies Medical Center, San Francisco: Brian Christianson, R.N., Linette Engel, Ed Freeman, R.N., Michael Lowder, R.R.T., Byron Morgenroth, R.R.T., Kathy Murray, R.R.T., Robert Wong, R.R.T.; East Bay AIDS Center, Oakland: Bruce Brown, R.N., Ann Steinlauf, R.N.; Marin General Hospital, San Rafael: Dale Parks, R.R.T.; Mt. Zion Hospital, San Francisco: Julio Barba, R.R.T., Jill Heath, R.R.T.; Pacific Presbyterian Medical Center, San Francisco: John Duda, R.R.T., Joe Fortney, R.R.T., Kathy Kandal, R.R.T., Paige Kelly, R.R.T., Paul Starzyk, R.R.T., Spencer Thompson, R.R.T.; Peralta Adult Immunology Clinic, Oakland: Michael Chiu, R.R.T., David Greenberg, R.N., Rima Rhodes; Santa Rosa Community Hospital, Santa Rosa: Maggie Brock, John Clarke, R.R.T., Tom Fritz, R.R.T.; San Francisco General Hospital, San Francisco: Deb Gumley-Smith, Bobby Terrell, R.R.T., Robbie Wong. Pharm, D.; St. Luke's Hospital, San Francisco: Max Huang, R.R.T., Chuck Paden, R.R.T.; University of California, San Francisco: Barbara Newlin, N.P., Hal Smith; Fort Miley Veterans Affairs Medical Center, San Francisco: Sandy Charles, R.N., Sheila Graf, R.N.
Data-coordinating centers: San Francisco General Hospital: Robin Edison, M.D., M.P.H., Erin McGinty, R.N., David Townley, James Henry; New Drug Services: Cathy Miller, Beverly Harrison, R.N., Dana Scott, Ph.D.
Source Information
From the AIDS Activities Division, the Medical Service, San Francisco General Hospital; and the Department of Medicine (G.S.L., D.W.F., K.C., L.W., M.A.J.. P.A.V., D.A.), and the Department of Epidemiology and Biostatistics (D.W.F), School of Medicine. University of California; Children's Hospital (D.B.); and Pacific Medical Center (S.G.), all in San Francisco; the Department of Medicine. State University of New York at Stony Brook (A.B.M.); and New Drug Services, Chadds Ford, Pa. (M.A). Address reprint requests to Dr. Feigal at the Department of Medicine, University of California at San Diego Medical Center, 225 Dickinson St. H811E, San Diego, CA 94103.
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