Original Article
A Controlled Trial Comparing Continued Zidovudine with Didanosine in Human Immunodeficiency Virus Infection
N Engl J Med 1992; 327:581-587August 27, 1992
- Abstract
- Abstract
Background.
Although zidovudine is effective in patients with human immunodeficiency virus (HIV) infection, its efficacy may decline with prolonged use. Didanosine is another inhibitor of HIV reverse transcriptase. We evaluated the effectiveness of changing anti-HIV treatment from zidovudine to didanosine.
Methods.
This multicenter, double-blind study involved 913 patients who had tolerated zidovudine for at least 16 weeks. The patients had the acquired immunodeficiency syndrome (AIDS), AIDS-related complex with ≤300 CD4 cells per cubic millimeter, or asymptomatic HIV infection with ≤200 CD4 cells per cubic millimeter. They were randomly assigned to receive 600 mg per day of zidovudine, 750 mg per day of didanosine, or 500 mg per day of didanosine.
Results.
There were significantly fewer new AIDS-defining events and deaths among the 298 subjects assigned to 500 mg per day of didanosine than among the subjects who continued to receive zidovudine (relative risk, 1.39; 95 percent confidence interval, 1.06 to 1.82; P = 0.015). With 750 mg of didanosine, there was no clear benefit over zidovudine (relative risk, 1.10; 95 percent confidence interval, 0.86 to 1.42). The efficacy of didanosine was unrelated to the duration of previous zidovudine treatment. In the two didanosine groups, there were improvements in the number of CD4 cells (P<0.001 for both groups) and in p24 antigen levels (P = 0.03 in the 500-mg group; P = 0.005 in the 750-mg group), as compared with the zidovudine group.
Conclusions.
Changing treatment from zidovudine to 500 mg per day of didanosine appears to slow the progression of HIV disease. (N Engl J Med 1992;327:581–7.)
Media in This Article
Figure 1
Probability of a New, Nonrecurrent AIDS-Defining Event or Death in the Three Study Groups.Table 1
Base-Line Characteristics of the Study Subjects at the Time of Randomization into the Three Treatment Groups.Article Activity
- Article
THE nucleoside analogue zidovudine (3′-azido-3′deoxythymidine) inhibits human immunodeficiency virus (HIV) replication and is more effective than placebo in delaying death in subjects with the acquired immunodeficiency syndrome (AIDS), in delaying the development of AIDS in subjects with AIDS-related complex, and in delaying the development of AIDS or AIDS-related complex in subjects with asymptomatic HIV infection.1 2 3 4 Mortality was reduced with early use of zidovudine with or without prophylaxis against Pneumocystis carinii pneumonia,5 , 6 although these data are controversial.7 The duration of the clinical usefulness of zidovudine is unknown, and drug failure, manifested by the progression of HIV disease, presents a challenge in the care of HIV-infected persons. In vitro susceptibility of HIV isolates to zidovudine suggests that resistance develops at variable rates, depending on the clinical stage of disease, the level of CD4 cells, and the duration of zidovudine therapy.8 9 10 11 12 13 The efficacy of zidovudine might diminish because of HIV resistance, intolerance to the therapy,14 , 15 or direct toxicity to lymphocytes.16
Didanosine (2′,3′-dideoxyinosine) is also a nucleoside analogue that inhibits HIV reverse transcriptase, displays anti-HIV activity in vitro, and in early clinical trials has appeared to be active against HIV viral isolates resistant to zidovudine.17 18 19 20 21 22 23 24 The major toxic effects of didanosine differ from those of zidovudine.14 , 15 , 25 , 26 In the fall of 1991, didanosine was approved for the treatment of persons in whom zidovudine treatment had failed or who had become intolerant to zidovudine.
The current study was designed to determine whether changing from zidovudine to didanosine reduces the risk of subsequent AIDS-related events or death as compared with continued zidovudine treatment. In October 1989, the AIDS Clinical Trials Group (ACTG) began two trials, ACTG 116 and ACTG 117, that had similar designs, eligibility requirements, and drug dosages, but that differed with respect to the duration of previous zidovudine therapy (<48 weeks and ≥48 weeks, respectively). In November 1990, before any examination of the study results, protocols 116 and 117 were reorganized as ACTG 116A (<16 weeks of previous zidovudine therapy) and ACTG 116B/117 (≥16 weeks of previous zidovudine therapy). We present the data from the latter study in this report.
Methods
Study Design
ACTG 116B/117 was a multicenter, randomized, double-blind trial that compared the clinical efficacy and safety of zidovudine with those of didanosine in subjects who had tolerated at least 16 weeks of zidovudine. The subjects were randomized according to institution in a permuted-blocks design and were stratified according to base-line CD4 count (ACTG 117) and diagnosis (ACTG 116).
Patient Population
Male and nonpregnant female patients at least 12 years of age were eligible to enter ACTG 116B/117 if they met the following criteria: HIV infection documented by enzyme-linked immunosorbent assay (ELISA); previous zidovudine therapy for at least 16 weeks (minimum daily dose, 500 mg); and two CD4 counts ≤300 cells per cubic millimeter (0.3 × 109 cells per liter) in the case of subjects with AIDS or AIDS-related complex or ≤200 cells per cubic millimeter (0.2 × 109 cells per liter) in the case of asymptomatic subjects. AIDS-related complex was defined according to clinical criteria determined previously.3 , 4 The study subjects were required to have a Karnofsky performance status of at least 60 percent and the following laboratory measures: a hemoglobin level above 8.5 g per deciliter, an absolute neutrophil count above 1.0 × 109 per liter, a platelet count above 75×109 per liter, a serum uric acid concentration ≤9.0 mg per deciliter (535 μmol per liter), serum creatinine concentration ≤1.5 times the upper limit of normal, serum amylase concentration ≤1.3 times the upper limit of normal, and serum concentrations of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase all ≤5 times the upper limit of normal. No patient had AIDS dementia complex more advanced than stage 1 at entry into the study,27 , 28 and all gave written informed consent for participation in the study.
Treatment Regimens and Concomitant Medication
Didanosine was provided in sachets containing 5.2 g of citrate—phosphate buffer and sucrose adjusted to yield a final net weight of 20 g. Every 12 hours, the contents of one sachet were dissolved in water and swallowed. Two weight-adjusted daily dosages of didanosine were studied: 750 mg (500 mg if the subject weighed less than 60 kg) and 500 mg (334 mg if the subject weighed less than 60 kg). The subjects assigned to didanosine received capsules of placebo resembling zidovudine every four hours. In the initial three months of the study, the subjects assigned to zidovudine continued their prestudy dose. In January 1990 a standard dose of zidovudine (100 mg every four hours, for a total daily dose of 600 mg) was initiated. Every 12 hours, the subjects assigned to zidovudine received a sachet containing buffer and sucrose to serve as a didanosine placebo.
The subjects were asked to continue their assigned treatments until the occurrence of a new AIDS-defining event or severe or recurrent side effects, and they were followed to the close of the study or death. The management of toxic effects was decided in advance according to type of effect, severity, and organ system affected. Any subject who had a new, nonrecurrent AIDS event or recurring toxicity requiring permanent discontinuation of the study drug was offered the option of a blinded crossover to the opposite therapy. Any subject with serious symptoms or laboratory abnormalities had the study medications (and placebo) withheld until the symptoms or laboratory abnormalities resolved, at which point the subject resumed the study medications at a reduced dose, discontinued them altogether, or changed to the other study drug.
Treatment with aerosolized pentamidine (300 mg every four weeks, using a Respigard II nebulizer) was required for all study participants. Alternative prophylaxis was permitted in the event of intolerance to aerosolized pentamidine. Long-term suppressive therapy for previously diagnosed opportunistic infections was permitted.
Clinical End Points
The primary end point for subjects with AIDS-related complex and subjects with asymptomatic HIV infection was progression to an AIDS-defining event (according to the revised criteria of the Centers for Disease Control [CDC],29 but excluding Kaposi's sarcoma and stage 1 AIDS dementia) or death. The primary end point for subjects with AIDS was progression to a new, nonrecurrent AIDS-defining event29 or death. All reports of primary end points were reviewed by monitors at the site and confirmed in a blinded manner by the protocol chairman. Cases of AIDS dementia complex and progressive multifocal leukoencephalopathy were reviewed by the protocol neurologist. Secondary end points included the development of either a new or a recurrent AIDS-defining event and changes in CD4 cell counts and p24 antigen status.
Evaluation of Subjects and Follow-up
After the base-line evaluation, the subjects were scheduled to be seen at week 2, at week 4, and then monthly. They were seen more frequently if toxicity developed or if a visit was clinically indicated. Hematologic studies, serum-chemistry measurements, and studies of liver and renal function were obtained at weeks 2, 4, and 8 and then monthly. CD4 cell counts and serum p24 antigen assays were performed at weeks 2, 8, 12, and 16 and then every two months. Random serum samples were collected to assay didanosine levels.
HIV p24 Antigen Assay and Study-Drug Quantitation in Serum
For the subjects at ACTG sites, assays of HIV p24 antigen were performed in batches by ELISA from frozen serum aliquots (Abbott, Chicago).30 Assays of HIV p24 antigen for the subjects at four other sites were not batched. A positive test was defined as one that detected an antigen level above 10 pg per milliliter. Quantitation of didanosine in human plasma was performed by high-performance liquid chromatography.
Statistical Analysis and Interim Data Monitoring
The treatment groups were compared with respect to base-line variables by a Wilcoxon rank-sum test or by Fisher's exact test. Intention-to-treat analysis was used in the analysis of clinical end points, CD4 cell counts, and p24 antigen levels. Data on toxic effects were censored after a crossover and 30 days after the discontinuation of the initial treatment. Comparisons between treatment groups with respect to primary and secondary clinical end points and toxicity were based on the use of time-to-failure methods, including Kaplan–Meier estimators, stratified log-rank tests, and stratified proportional-hazards regression models, with stratification according to CD4 count (<100 vs. ≥100 cells per cubic millimeter) and disease stage (AIDS vs. AIDS-related complex or asymptomatic HIV infection) at the time of randomization.31 32 33 34 Changes in CD4 cells and p24 antigen response rates were analyzed as previously described.35 All P values reported are two-sided.
Interim analyses of the study, performed according to prespecified stopping rules, were presented to the ACTG Data and Safety Monitoring Board in February and August 1991. After each presentation, the board recommended that the study continue as originally planned. Apart from the members of the board, access to the study results was limited to the study statisticians and the medical officer of the National Institutes of Health until after the final scheduled visits by the subjects and the assessment of end points.
Results
Patient Accrual and Eligibility and Duration of Follow-up
The study began in October 1989. The accrual of subjects was completed in April 1991, and follow-up ended in November 1991. A total of 913 subjects were randomized (Table 1Table 1
Base-Line Characteristics of the Study Subjects at the Time of Randomization into the Three Treatment Groups.). Fourteen subjects had major violations of the eligibility criteria, and an additional 80 subjects had minor violations of the criteria. The analyses are based on all 913 randomized subjects, of whom 311 were assigned to the 750-mg daily dose of didanosine, 298 to the 500-mg daily dose of didanosine, and 304 to zidovudine. The average length of follow-up from the time of randomization was 55 weeks, and this length did not differ among the three treatment groups. Forty-eight subjects (5 percent) were lost to follow-up before reaching a primary end point. The distribution of time until loss to follow-up was similar (P = 0.48) in the three treatment groups.Base-Line Characteristics
The subjects were primarily male (96 percent), white (82 percent) (Table 1), and homosexual or bisexual (79 percent). Their median age was 36 years. Before randomization, the subjects' median duration of zidovudine therapy was 13.9 months, and virtually all the subjects continued to receive zidovudine up to the time of screening for this study. Overall, 93 percent of the subjects received prophylaxis against P. carinii pneumonia at the start of therapy, with 81 percent receiving aerosolized pentamidine. Of the 913 subjects, 30 percent (270 subjects) had a previous AIDS event, 60 percent (552) had a previous diagnosis of AIDS-related complex, and 10 percent (91) were asymptomatic. The median CD4 counts at entry were 45 cells per cubic milliliter for the subjects with AIDS, 119 for those with AIDS-related complex, and 112 for those with asymptomatic infection. The subjects with AIDS also tended to have lower hemoglobin levels, white-cell counts, and Karnofsky performance status than those with AIDS-related complex or asymptomatic infection at entry. The three treatment groups were well balanced with respect to all base-line characteristics measured.
Duration of Treatment and Voluntary Withdrawal
A total of 389 subjects (43 percent) received the study medication until the protocol was closed. Of these subjects, 126, 143, and 120, respectively, were assigned to the 750-mg didanosine group, the 500-mg didanosine group, and the zidovudine group. The rate of voluntary withdrawal from the study drug in the zidovudine group was significantly higher than the rates in the 750-mg (P = 0.03) and 500-mg (P = 0.001) didanosine groups. The rate of withdrawal in the subjects assigned to the 750-mg dose of didanosine was higher, but not significantly so, than that in the subjects in the 500-mg group (P = 0.15). Voluntary withdrawal from therapy according to the protocol was significantly correlated with lower initial CD4 counts (P = 0.016) and a pretreatment diagnosis of AIDS (P = 0.01). The most commonly stated reason for voluntary discontinuation of treatment was the wish to receive another antiviral agent.
Progression to Clinical End Points
Among the 311 subjects assigned to 750 mg of didanosine, the 298 subjects assigned to 500 mg of didanosine, and the 304 subjects assigned to continue receiving zidovudine, 115, 94, and 125 subjects, respectively, had a new, nonrecurrent AIDS-defining event or died. These rates correspond to progression rates of 41, 34, and 48 events per 100 person-years of observation in the respective groups (Table 2Table 2
Incidence of Clinical Events According to Treatment Group.* and Fig. 1Figure 1Probability of a New, Nonrecurrent AIDS-Defining Event or Death in the Three Study Groups.A). As compared with the subjects receiving zidovudine, the subjects receiving 500 mg of didanosine had lower rates of new AIDS events and deaths (P = 0.015), of new and nonrecurrent AIDS diagnoses (P = 0.005), and of new or recurrent AIDS events or death (P = 0.02). For these end points, the progression rates among the subjects in the 750-mg didanosine group trended in the same direction as those in the 500-mg didanosine group but did not differ significantly from the rates in the zidovudine group. There was no significant difference in mortality between the three treatment groups.Among the 287 patients who had a new or recurrent AIDS-defining event during the study, P. carinii pneumonia was the most common such event, followed by invasive candidiasis and cytomegalovirus infection (Table 3Table 3
New AIDS-Defining Events According to Treatment Assignment.*). During the study, the use of prophylaxis against P. carinii pneumonia was widespread in all three treatment groups, with 93, 97, 97, 96, and 92 percent of subjects receiving it at base line and during months 3, 6, 9, and 12 of the study, respectively. There was no difference in the distribution of such prophylaxis between the three treatment groups during the study.New and nonrecurrent P. carinii pneumonia developed in a total of 51 subjects, and in 14 of these, the diagnosis was made more than 30 days after the subject discontinued the study medication (3 patients assigned to the 750-mg didanosine dose, 5 patients assigned to the 500-mg didanosine dose, and 6 patients assigned to zidovudine). Of the remaining 37 subjects in whom P. carinii pneumonia developed, all but 3 (each of whom was assigned to zidovudine) had been receiving prophylaxis against pneumonia of this type.
The lower rate of clinical events in the 500-mg didanosine group as compared with the zidovudine group was observed primarily in the subjects with AIDS-related complex and the asymptomatic subjects (relative risk, 1.83; 95 percent confidence interval, 1.27 to 2.63; P = 0.001) (Fig. 1B). Similarly, among the subjects who entered the study with AIDS-related complex or asymptomatic HIV infection, the rate of new AIDS-defining events and deaths was significantly lower in the 750-mg didanosine group than in the zidovudine group (relative risk, 1.46; 95 percent confidence interval, 1.03 to 2.06; P = 0.02). In contrast, among the subjects who entered the study with a previous diagnosis of AIDS, there was no suggestion of a difference between the three treatment groups in the rates of reaching the primary end point.
There was no evidence of a trend in the efficacy of didanosine as compared with zidovudine with increasing duration of zidovudine therapy before the study (P = 0.7). Advanced stage of disease at base line (P<0.001), Karnofsky performance status (P = 0.001), and lower CD4 cell counts (P = 0.001) were significantly correlated as independent variables with the increased risk of a primary end point. The significant differences between treatments noted in Table 2 remained after we controlled for these factors in a multivariate proportional-hazards analysis.
Changes in CD4 Cell Counts and HIV p24 Antigen Levels
In the subjects receiving didanosine, CD4 cell counts increased during the initial 8 to 12 weeks of therapy and then began to decline. In the subjects treated with zidovudine, CD4 counts tended to decline throughout the study period; these subjects had an average of 12 to 15 fewer cells per cubic millimeter than the subjects in both didanosine groups (P<0.001 for both) during the first 24 weeks of therapy (Table 4Table 4
CD4 Cell Counts and HIV p24 Antigen Responses, According to Treatment Group.). Beyond week 24, there were progressively fewer samples of CD4 cells, making comparisons performed at these later times difficult to interpret. Among the subjects initially positive for serum p24 antigen, significantly higher proportions of those in the 750-mg and 500-mg didanosine groups had p24 antigen levels that declined by at least 50 percent (P = 0.005 and P = 0.03, respectively, as compared with the zidovudine group).Safety Data
The median times to a first modification of the dose, including a reduction in or discontinuation of the study drug, were 33, 39, and 27 weeks for subjects assigned to receive 750 mg of didanosine, 500 mg of didanosine, and zidovudine, respectively. Severe anemia was uncommon in all groups and was less common in the group receiving 750 mg of didanosine (P<0.04) than in the zidovudine group (Table 5Table 5
Laboratory and Clinical Toxic Effects of the Study Drugs.). Recipients of the 750-mg didanosine dose had less severe leukopenia (P = 0.001) and granulocytopenia (P = 0.007) than recipients of zidovudine. Treatment with the 500-mg dose of didanosine was associated with less severe granulocytopenia (P = 0.004) than treatment with zidovudine. The rate of pancreatitis was higher in the 750-mg didanosine group than in either the zidovudine group (P = 0.001) or the 500-mg didanosine group (P = 0.04). The number of cases of pancreatitis was higher in the 500-mg didanosine group than in the zidovudine group (17 and 6 subjects, respectively), but the difference was not statistically significant (P = 0.09). Fatal pancreatitis developed in two subjects receiving 750 mg of didanosine. The 750-mg and 500-mg didanosine groups both had greater increases in unfractionated serum amylase concentrations than the zidovudine recipients (P<0.001 and P = 0.001, respectively). The rate at which peripheral neuropathy of grade 2 or worse developed did not differ significantly between the three treatment regimens.Compliance with Study Medications
Compliance with the assigned study regimens was assessed by evaluating serum didanosine levels within six hours of the most recent sachet dose and by assessing the mean corpuscular volume of erythrocytes. Of the 70 subjects assigned to zidovudine whose didanosine levels were tested, 1 (1 percent) had detectable levels of didanosine. In contrast, 79 percent of 159 serum samples drawn from subjects assigned to didanosine had detectable levels of the drug. The median value for mean corpuscular volume in all subjects at base line was 110 μm3. In subjects who continued to receive zidovudine, this value remained high. However, the median values for mean corpuscular volume in the subjects randomly assigned to didanosine decreased to 89 μxm3.
Discussion
The major clinical question evaluated in this trial was whether subjects who had tolerated at least 16 weeks of zidovudine should continue zidovudine or change to didanosine. The subjects were people with AIDS or AIDS-related complex and CD4 counts below 300 cells per cubic millimeter, as well as asymptomatic people with CD4 counts below 200 cells per cubic millimeter. In 913 subjects followed for an average of 14 months, a new, nonrecurrent AIDS-defining event or death occurred in 115 subjects assigned to receive 750 mg of didanosine per day (37 percent), 94 subjects assigned to receive 500 mg of didanosine per day (32 percent), and 125 subjects assigned to receive zidovudine (41 percent). The incidence of these events was significantly lower in the 500-mg didanosine group than in the zidovudine group (P = 0.015). In the subjects with AIDS-related complex and the asymptomatic subjects, treatment with didanosine, as compared with zidovudine, significantly delayed the first new AIDS-defining event or death (P = 0.001 for the 500-mg didanosine group and P = 0.006 for the 750-mg group). There were no differences according to treatment group among the subjects who entered the study with AIDS, or among all patients with respect to death.
There were higher rates of severe anemia and leukopenia with zidovudine than with didanosine. There were significantly higher rates of hyperamylasemia and pancreatitis in the 750-mg didanosine group than in the zidovudine group. The rates of pancreatitis in the 500-mg didanosine group and the zidovudine group did not differ significantly. The rates of peripheral neuropathy did not differ between treatment groups.
Criteria for clinical failure were rigorously applied without knowledge of treatment-group assignment; therefore, it is likely that the superiority of didanosine to zidovudine in relation to the primary end points is valid. Furthermore, similar results were obtained after ineligible patients were excluded and after unconfirmed and unverified end points were included.
The reasons for a lack of clinical efficacy among subjects with AIDS are unclear, but these subjects were more likely than those without AIDS to discontinue the study treatment. Premature discontinuation of therapy according to the protocol would tend to decrease the sensitivity of this trial for detecting a difference between study treatments.36 Thus, voluntary discontinuation of treatment may have contributed to the lack of a difference between treatments in these patients. In addition, the study was not designed to have the power to evaluate the effects of therapy in the subgroup of patients with AIDS.
The data from this trial indicate that subjects randomly assigned to the 500-mg didanosine group had a significantly lower rate of new AIDS-defining events, and that at this dose, didanosine had an acceptable toxicity profile as compared with zidovudine. The somewhat better rate of clinical efficacy in the 500-mg didanosine group as compared with the 750-mg didanosine group appears inconsistent with the observed changes in CD4 counts and p24 antigen levels. However, clinical-event rates for subjects in the 750-mg didanosine group trended in the same direction as rates in the 500-mg group. Improved rates of clinical efficacy in the 500-mg didanosine group may have been partly due to greater clinical tolerance for the lower didanosine dose; fewer patients in this group opted to discontinue the study medication. Other large trials have reported similar patterns, in which lower doses are associated with less discontinuation of treatment and better clinical efficacy.4 , 37
The benefit from didanosine observed in this study may simply demonstrate the advantage of changing from one effective nucleoside to another, rather than continuing treatment with a single well-tolerated drug. Questions about the optimal scheduling of antiretroviral nucleosides, the alternation of drug regimens, and the clinical usefulness of using antiretroviral treatments in combination all require further investigation. The results of this trial suggest that the role of didanosine should not be limited to persons who do not tolerate zidovudine therapy or in whom such therapy has failed; rather, they support the expanded use of didanosine in the defined study population.
*The contributing members of the AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases (NIAID) and the independent investigators are listed in the Appendix.
Source Information
From San Francisco General Hospital and the University of California, San Francisco (J.O.K., P.A.V.); the Harvard School of Public Health, Boston (S.W.L., S.L.); the University of California and the Veterans Affairs Medical Center, San Diego, Calif. (D.D.R.); Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Conn. (A.C., M. Brown, M. Beltangady, L.S.); the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (C.P.); Harvard University, Boston (C.S.C.); Harbor–UCLA Medical Center, Torrance, Calif. (G.B.); Mount Sinai School of Medicine, New York (H.S.S.); Stanford University, Stanford, Calif. (T.C.M.); and the University of Rochester, Rochester, N. Y. (R.D.). Address reprint requests to Dr. Kahn at the AIDS Program, Ward 84, San Francisco General Hospital, 995 Potrero Ave., San Francisco, CA 94110.
Appendix
The following persons and institutions participated in the ACTG 116B/117 trial. Administrative Center (NIAID, Division of AIDS): J. Jermano and S. Falen; Randomization Center (Frontier Science and Technology Research Foundation): B. Lunghofer; University of California, San Francisco — L.Johnson, P. Joseph, H. Hollander, and R. Coleman; Harvard University, Cambridge, Mass. — T. Cooley, M.S. Hirsch, K. Shea, G. Ray, and R.T. Schooley; UCLA School of Medicine — W.D. Hardy, B. Manchester, and R.T. Mitsuyasu; University of Rochester Medical Center, Rochester, N.Y. — D. Blair, R. Hewitt, and J. Reid; Mt. Sinai School of Medicine, New York — C. Alder, C. Sanders, J. Jacobson, and G. Simpson; Stanford University School of Medicine, Stanford, Calif. — D. Katzenstein, J. Fessel, P. Cain, and B. Carr; St. Luke's–Roosevelt Hospital, New York — G.F. McKinley, M.H. Grieco, and B.R. Kolatch; New York University Medical Center, New York — V.J. McAulifle, C. Farthing, F.T. Valentine, and V. Rosenwald; George Washington University Medical Center, Washington, D.C. — G.L. Simon, D.M. Parenti, and B.R. Lewis; University of Washington, Seattle — A.C. Collier, A. Wald, M. Paradise, and L. Corey; University of Southern California, Los Angeles — M. Liggins, B. McNamera, N. Quesada, and B. Akil; University of California, San Diego — L.S. Rickman, S.A. Spector, E.M. Hayden, and JA. Schnack; Northwestern University, Chicago — H.A. Kessler, R.L. Murphy, J.C. Pottage, Jr., and C.A. Benson; Albert Einstein College of Medicine, New York — H. Ingelfinger, P. Kahl, D. Stein, and E. Jenny; Memorial Sloan-Kettering Cancer Center, New York — E. Telzak, K. Somogyi, M. Carrow, and W. Proper; State University of New York at Stony Brook — R. Steigbigel, J. Fuhrer, M.E. Roarke, and R.A. Burke; Case Western Reserve University, Cleveland — M. Lederman, J. Carey, M. Chance, and T. Davis; Tulane University School of Medicine, New Orleans — J. Zachary, D. Mushatt, D. Hoadley, and N. Hyslop, Jr.; University of Pittsburgh, Pittsburgh — M. Ho, D. McMahon, G.J. Pazin, and J.A. Armstrong; Washington University School of Medicine, St. Louis — W. Powderly, L. Gelb, A. Slack, and M.L. McGuire; University of Texas, Galveston — R. Pollard, S. Roquemore, D. Winder, and K. Jinkins; Ohio State University, Columbus — M. Para, R. Fass, M.James, and J. Neidig; Hershey Medical Center, Hershey, Pa. — W.C. Ehmann, J.J. Zurolo, R. Millard, and M. Kreher; Duke University, Durham, N.C. — K.D. Rayle, L.M. Stewart, and H.A. Waskin; University of Miami, Miami — M. Fischl, G. Daikos, J. Cole, and P. Smith, Jr.; University of Minnesota, Minneapolis — A. DePalois-Jones, B.K. Goodroad, F.S. Rhame, and W.K. Henry; University of Massachusetts, Worcester — S. Cheeseman, R. Haubrich, K. Toison, and C.A. Bova; Johns Hopkins University, Baltimore — R. Becker, S. Coton, L. Grue, and K. Mayjo; University of North Carolina, Chapel Hill — C. van der Horst, A. Heggen-Snow, E. Wallmark, and S. Fiscus; Indiana University, Indianapolis — P. Hartman, J. Craft, and K. Fife; St. Joseph's Hospital, Tampa, Fla. — B.G. Yangco and V. Kenyon; Cornell University, Ithaca, N.Y. — H.W. Murray; Robert Wood Johnson Medical Center, New Brunswick, N.J. — D.J. Gocke and C. Miner; Northeastern Wisconsin Hemophilia Treatment Center, Green Bay — S. Adair, J. Lacey, and P. Maier; Hemophilia Treatment Center, St. Francis Hospital, Peoria, Ill. — E. Czapek and M. Green; and University of Utah, Salt Lake City — S.L. Spruance, K.M. Ries, T.G. Evans, and A.T. Pavia.
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