Original Article
A Randomized Controlled Trial of a Reduced Daily Dose of Zidovudine in Patients with the Acquired Immunodeficiency Syndrome
N Engl J Med 1990; 323:1009-1014October 11, 1990
- Abstract
- Abstract
Background.
The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity.
Methods.
To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262).
Results.
The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the standard-treatment group and 34 percent for the lowdose group (P = 0.033). In both groups, 82 percent of the subjects had another opportunistic infection, and the length of time to that infection was similar in the two groups (P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved transiently in both groups, and serum levels of HIV antigen decreased in the subjects with antigenemia. The hemoglobin level declined to less than 5 mmol per liter (80 g per liter) in 101 subjects in the standard-treatment group and in 77 in the low-dose group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The neutrophil count declined to less than 0.750×109 per liter in 134 subjects in the standard-treatment group and in 96 in the low-dose group (51 vs. 37 percent, P = 0.0001).
Conclusions.
The reduced daily dose of zidovudine used in this study was at least as effective as the standard dose and was less toxic; however, with the use of a four-week induction period with a high dose followed by low-dose treatment, severe anemia and neutropenia were common complications of treatment with zidovudine. (N Engl J Med 1990; 323:1009–14.)
Media in This Article
Figure 1
Estimated Distributions of Lengths of Time to Death, According to Treatment Group.Figure 2
Estimated Distributions of Lengths of Time to Occurrence or Recurrence of an Opportunistic Infection.Article Activity
- Article
ZIDOVUDINE (3′-azido-3′-deoxythymidine; formerly azidothymidine, or AZT) is a thymidine analogue that inhibits the replication of the human immunodeficiency virus type 1 (HIV) in vitro.1 The administration of zidovudine to patients with advanced HIV disease over a 6-to-24-month period prolongs survival, decreases the frequency and severity of opportunistic infections, improves neurologic function, transiently improves CD4 T-lymphocyte counts, and decreases the rate of HIV antigenemia.2 3 4 5 6 7 8
Despite these benefits, zidovudine therapy is frequently associated with adverse reactions, including both anemia and neutropenia.2 , 9 Although the serum half-life of zidovudine is one hour, the intracellular half-life of its 5′-triphosphate form approaches three hours, suggesting that lower daily doses or longer intervals between drug administration may be adequate.
To evaluate the safety and efficacy of a lower daily dose of zidovudine, we conducted a randomized, controlled trial in which the initially tested dose of zidovudine (250 mg every four hours)2 was compared with a lower dose (100 mg every four hours). This report details the preliminary findings of the study.
Methods
Study Population
The study population consisted of subjects who had had a first episode of histologically confirmed Pneumocystis carinii pneumonia at least two weeks before enrollment. Subjects who had previously received zidovudine, who had had multiple episodes of P. carinii pneumonia, or who had any further infection or a neoplasm indicating the presence of the acquired immunodeficiency syndrome (AIDS), other than minimal cutaneous Kaposi's sarcoma, were excluded. The criteria for eligibility also included a hematocrit of 30 percent or more, a total neutrophil count of 1.0×109 per liter or more, a platelet count of 75×109 per liter or more, a serum aspartate or alanine aminotransferase level that was less than five times the upper limit of normal, a Karnofsky performance score of 60 or more, and serum positive for HIV antibody as determined with any licensed enzyme-linked immunosorbent assay. The use of other anti-HIV drugs, biologic-response modifiers, prophylaxis for P. car- inii pneumonia, or systemic corticosteroids was not allowed. The study was revised in August 1987, to allow the use of prophylaxis for P. carinii pneumonia after a second episode of this complication, and in April 1988, to allow the use of inhaled pentamidine in any subject.
The study subjects were recruited from 18 AIDS Clinical Trials Group units in the United States. The study was approved by institutional review boards at each unit, and all subjects gave written informed consent.
Evaluation of Subjects
The pretreatment evaluation included a medical history, a physical examination, and the following laboratory studies: the measurement of the hematocrit, hemoglobin, mean corpuscular volume, white-cell count, differential white-cell count, platelet count, and reticulocyte count; serum chemistry determinations; renal-function and liver-function tests; urinalysis; chest roentgenography; quantitation of T-lymphocyte subsets; and determination of serum levels of HIV antigen. HIV-antigen levels were measured by antigen-capture assay (Abbott Laboratories, N. Chicago) in which purified virion p24 (ACTG Virology Reference Laboratory, Houston) was used as a calibration standard. Serum was considered to contain detectable levels of antigen if the concentration was more than 25 pg per milliliter. All serum samples were stored at — 70°C until analysis, and all were tested simultaneously. All procedures were standardized and performed under quality control.
The subjects were reevaluated at specified intervals and were monitored for adverse events. Subjects who were withdrawn from their study medication were followed for disease progression and survival. First clinical end points and study eligibility were verified by independent monitors who used source documents at each unit. Clinical measures of the efficacy of a lower daily dose of zidovudine included survival and disease progression, which was defined as the development of another AIDS-defining opportunistic infection, Kaposi's sarcoma, or a high-grade B-cell lymphoma. Increases in CD4 T-lymphocyte counts and decreases in serum HIV-antigen levels were used as secondary measures.
Treatment Regimen
The study was designed as an open-label, randomized, controlled trial. A blocked-randomization procedure was used to assign subjects randomly within each unit to receive one of two daily doses of zidovudine. Zidovudine was given either in one 250-mg capsule every four hours (standard-treatment group) or in one 200-mg capsule every four hours for a total of four weeks, followed by 100 mg every four hours (low-dose group).
If serious treatment-related toxic reactions occurred, administration of the study medication was interrupted until abnormal values returned to levels indicating a lower grade of toxicity or to base-line levels. If severe anemia developed, red-cell transfusions were given. If subjects had a persistent serious toxic reaction, a toxic reaction that recurred after a two-step dose reduction, or a life-threatening toxic reaction, their study medication was stopped.
Statistical Analysis
The statistical significance of differences in proportions was determined with the chi-square test or the Fisher exact test.10 The distributions of ordinal and continuous measurements were compared by means of the Wilcoxon—Mann—Whitney test.11 The distributions of lengths of time to events were estimated according to the method of Kaplan and Meier,12 and comparisons of these distributions among groups were made with both the log-rank test and the Wilcoxon test.13 , 14 All analyses were based on an intention-to-treat approach and on data available through October 6, 1989. All P values are two-sided.
In an attempt to assess the relation between the use of prophylaxis for P. carinii pneumonia and survival, a series of landmark analyses were conducted. Among subjects alive at six months, those who received prophylaxis during the first six months of the study and those who did not were compared with respect to subsequent survival. Subjects were stratified according to the recurrence of P. carinii pneumonia during the first six months. In addition, subjects in each treatment group were compared in terms of subsequent survival, with stratification for recurrent P. carinii pneumonia and for prophylaxis against it. Similar analyses were conducted at 8 months and 10 months.
Results
Study Population
Between December 2, 1986, and November 12, 1987, 560 subjects were enrolled in the study. Eight subjects (5 in the standard-treatment group and 3 in the low-dose group) did not meet the eligibility requirements for study entry, and all 28 subjects enrolled at one unit (14 in each treatment group) were lost to follow-up shortly after enrollment and were excluded from the data analysis; therefore, 524 subjects were included in the analysis. Four hundred ninety-five subjects were men, and 25 were women; their mean age was 36.9±8.5 years. Three hundred ninety-two subjects were white, 44 were black, 79 were Hispanic, and 5 belonged to other racial or ethnic groups. Demographic data were not available for four subjects.
Two hundred sixty-two subjects were assigned to receive a total daily dose of 1500 mg of zidovudine (standard-treatment group), and 262 to receive a total daily dose of 600 mg after a four-week induction period at a dose of 1200 mg per day (low-dose group). No significant differences were noted between the two treatment groups in their pretreatment characteristics (Table 1Table 1
Selected Characteristics of the Treatment Groups.*). The median length of follow-up in all subjects was 25.6 months, ranging up to 32.5 months. Forty-one subjects were still receiving their study medication when the treatment phase of the study was closed in July 1989. The median duration of study treatment was 8.3 months, ranging up to 31.5 months. The mean (±SD) and median cumulative doses of zidovudine received by subjects in the standard-treatment group were 266.1±240.8 g and 204.5 g, respectively, and the mean and median doses in the low-dose group were 191.5±136.9 g and 169.1 g, respectively (P = 0.007).Of the 524 subjects enrolled, 4 never received zidovudine, 41 completed the study, and 479 were withdrawn from zidovudine treatment. The reasons for withdrawal from zidovudine were the development of an opportunistic infection or a neoplasm requiring treatment that was not allowed by the study protocol (54 subjects); death (43); toxic reactions (183; 106 in the standard-treatment group and 77 in the low-dose group); withdrawal by the subject (169; 77 in the standard-treatment group and 92 in the low-dose group); and other reasons (30). Thirty-seven subjects were lost to follow-up (16 in the standard-treatment group and 21 in the low-dose group, P = 0.51 by the log-rank test).
Clinical End Points
Three hundred fifty-seven subjects (68 percent) died (188 [72 percent] in the standard-treatment group and 169 [65 percent] in the low-dose group). A statistically significant improvement in survival was noted in the low-dose group (P = 0.019 by the Wilcoxon test) (Fig. 1Figure 1
Estimated Distributions of Lengths of Time to Death, According to Treatment Group.). The estimates of survival at 12, 18, and 24 months were 76, 52, and 27 percent, respectively, for the standard-treatment group and 81, 63, and 34 percent, respectively, for the low-dose group. As shown in Figure 1, the survival curves of the two groups separated and then converged. The differences between the groups were significant after 12 months and remained significant at 18 months (P = 0.012 by the log-rank test) and 24 months (P = 0.033). Analysis of overall survival by the log-rank test resulted in a P value of 0.072.A further AIDS-defining opportunistic infection developed in 429 subjects (215 [82 percent] in the standard-treatment group and 214 [82 percent] in the low-dose group, P = 0.91). The difference between the two treatment groups in the length of time to the development of another opportunistic infection was not significant (P = 0.56 by the log-rank test) (Fig. 2Figure 2
Estimated Distributions of Lengths of Time to Occurrence or Recurrence of an Opportunistic Infection.). The types of opportunistic infections reported in the groups were not greatly different (Table 2Table 2
Adverse Clinical Events in the Treatment Groups.). Kaposi's sarcoma developed in 66 subjects (26 subjects [10 percent] in the standard-treatment group and 40 [15 percent] in the low-dose group, P = 0.07).Prophylaxis for P. carinii Pneumonia
Two hundred ninety-one subjects (56 percent) received prophylaxis for P. carinii pneumonia (131 [50 percent] in the standard-treatment group and 160 [61 percent] in the low-dose group). A significantly greater proportion of subjects in the low-dose group received prophylaxis earlier in the study, as compared with the proportion in the standard-treatment group (P = 0.015 by the log-rank test).
The estimated distribution of times to the recurrence of P. carinii pneumonia before the initiation of prophylaxis did not differ significantly in the two groups (P = 0.14 by the log-rank test). The estimated distribution of times to the occurrence of any clinical end point before the beginning of P. carinii prophylaxis also did not differ significantly in the groups (P = 0.27 by the log-rank test). The landmark analysis at six months showed no significant difference in subsequent survival between the subjects who received prophylaxis and those who did not. Similar results were observed in the landmark analyses at 8 months and 10 months. In relation to these same landmarks, survival was better in the low-dose group when subjects were stratified according to the recurrence of P. carinii pneumonia and use of prophylaxis.
Immunologic Data
In both treatment groups, the number of CD4 T lymphocytes increased significantly from pretreatment levels but declined to less than pretreatment levels by week 24. Similar changes occurred in the percentage of CD4 T lymphocytes. There were no statistically significant differences between the two groups in the number or percentage of CD4 T lymphocytes and the change from pretreatment levels (Fig. 3Figure 3
Median Changes in the Number of CD4 T Lymphocytes from Pretreatment Levels.).Virologic Data
Two hundred five subjects (of 406 tested [50 percent]) had detectable serum levels of HIV antigen before treatment (Table 3Table 3
HIV Antigenemia in the Treatment Groups.). A significant decline in HIV-antigen levels was noted among these subjects at week 8 and persisted throughout the study. No statistically significant differences were noted between the two treatment groups in antigen levels or the changes from pretreatment values. One hundred sixty-nine subjects (of 205 tested [82 percent]) who had detectable levels of antigen before therapy had an appreciable decrease in serum levels during treatment (Table 3). There was no difference between the two treatment groups in the length of time to a decrease in antigen levels (P = 0.74 by the log-rank test). Thirteen subjects (of 146 tested [9 percent]) who were negative for the HIV antigen before treatment later had detectable levels of antigen during the 128 weeks of treatment. There was no difference between the two treatment groups in the length of time to the observation of a detectable level of antigen (P = 0.11 by the log-rank test).Adverse Events
One hundred eighty-three subjects were withdrawn from zidovudine therapy because of toxic reactions. Zidovudine was discontinued earlier in more subjects in the standard-treatment group than in the low-dose group (106 subjects [40 percent] vs. 77 subjects [29 percent], P = 0.0001 by the log-rank test). Among the symptoms reported, only headache was noted more frequently in the low-dose group (205 subjects [78 percent] vs. 177 subjects [68 percent], P = 0.006).
Twenty-two subjects (8 percent) in the standard-treatment group and 27 (10 percent) in the low-dose group had elevated levels of hepatic enzyme (≥5.0 times the upper limit of normal for serum aspartate aminotransferase, P = 0.45). No statistically significant difference between the two groups was noted in the length of time to the first marked elevation of enzyme levels (P = 0.97).
One hundred seventy-eight subjects (34 percent) had a hemoglobin concentration below 5 mmol per liter (80 g per liter) (101 [39 percent] in the standard-treatment group and 77 [29 percent] in the low-dose group, P = 0.027). A greater proportion of subjects in the standard-treatment group had a first episode of severe anemia earlier in the study, as compared with the proportion in the low-dose group (P = 0.0009) (Fig. 4Figure 4
Estimated Distributions of Lengths of Time to a First Episode of Severe Anemia (A) (Hemoglobin <5 mmol per liter [80 g per liter]) or Neutropenia (B) (<0.750×109 per liter).A). One hundred thirty-four subjects (26 percent) received red-cell transfusions (65 in the standard-treatment group and 69 in the low-dose group, P = 0.69); the mean amount of cells transfused was 5.1±4.5 units in the standard-treatment group and 6.1±7.5 units in the low-dose group (P = 0.37).Two hundred thirty subjects (44 percent) had a neutrophil count below 0.750×109 per liter (134 [51 percent] in the standard-treatment group and 96 [37 percent] in the low-dose group, P = 0.0008). A greater proportion of subjects in the standard-treatment group had a first episode of severe neutropenia earlier in the study, as compared with the proportion in the low-dose group (P = 0.0001) (Fig. 4B).
Twenty-two subjects (4 percent) had a platelet count below 50×109 per liter. No statistically significant difference was noted between the two treatment groups in the number of patients with low platelet counts (P = 0.66). The mean corpuscular volume in both treatment groups increased from pretreatment levels; the maximal median was 110 fl, observed by week 32. No significant differences were observed between the two treatment groups in the mean corpuscular volume (P = 0.57, week 32).
Discussion
The findings in this study indicate that a lower daily dose of zidovudine is at least as effective in the treatment of patients with advanced HIV disease as the initially tested dose of 1500 mg per day and is less toxic. No differences in the length of time to the development of another opportunistic infection, the change in the CD4 T-lymphocyte count, or the decrease in the serum level of HIV antigen were noted during the low-dose therapy as compared with the standard treatment. Moreover, low-dose therapy was associated with a better survival rate. Survival benefits were noted after 12 months and persisted through 24 months of follow-up; after 24 months there were no differences between the two treatment groups. The reason for this better interim survival is not certain, but it is most likely related to the greater likelihood that continuous antiviral therapy can be maintained with lower doses of zidovudine. Progressive HIV disease and increasing mortality were observed during long-term follow-up, suggesting that the efficacy of zidovudine was waning. The reasons for this decline in efficacy are still unknown, but it may simply represent limitations of the drug and the advanced stage of disease in the subjects studied.
Although the isolation of zidovudine-resistant virus has been reported,15 no differences in the restriction of replication of HIV as measured by the rate of antigenemia were seen in the subjects given a lower dose of zidovudine. In addition, there was no increase in antigen levels late in the course of therapy, which might suggest a loss of viral efficacy. Although lower-than-standard doses of zidovudine were used, these data suggest that the current dose tested is still well within the range of therapeutic doses of the drug and that the use of this dose should not necessarily result in an increase in emergence of resistance. A recent study by Richman et al.16 confirmed that there were no differences between two groups given different doses in the rate of resistance.
The use of a lower dose of zidovudine was associated with less hematologic toxicity, and problems with severe anemia were less frequent. This should result in a better quality of life and a saving in health care costs among patients in whom anemia is likely to develop when they receive higher doses of zidovudine. As shown in several studies2 3 4 5 and in this study, the doselimiting toxic reaction associated with zidovudine therapy is neutropenia. Both the rate of severe neutropenia and the length of time to a first episode were reduced when a lower dose of zidovudine was given. Thus, a larger proportion of our subjects tolerated zidovudine, permitting a greater number to be treated over a longer period. This may have accounted for the better survival observed in the low-dose group.
Because of concerns that an increase in the HIV-antigen level may be associated with a decrease in the dose of zidovudine,17 we chose induction with a higher dose (200 mg every four hours for four weeks), followed by a lower dose (100 mg every four hours). The absence of differences between the two treatment groups and the better survival in the low-dose group demonstrate that low-dose therapy is effective. Since HIV infection is a chronic viral infection in which titers of circulating virus are higher when the disease is advanced,18 , 19 induction with a higher dose of the drug may not be needed in the light of the demonstrated efficacy of the lower dose. This is supported by the absence of any noticeable change in indexes of efficacy during the transition to a lower dose and the beneficial experience with a lower dose in patients with asymptomatic HIV infection.20 The use of a higher induction dose of zidovudine, however, may have contributed to the moderate level of toxicity nonetheless noted. Twenty-nine to 37 percent of subjects still had severe anemia or neutropenia. The toxic hematologic reactions observed occurred early in therapy, and the differences between the two treatment groups did not emerge until after the dose of drug was reduced in the low-dose group, suggesting that zidovudine can have toxic effects on bone marrow very early in therapy. Thus, it is likely that initiating zidovudine therapy with a lower dose will result in fewer toxic reactions than we observed in this study.
Zidovudine penetrates the cerebrospinal fluid, and the neurologic status of the patient can improve with therapy.6 However, the optimal dose of zidovudine for the treatment of patients with AIDS dementia complex has not been determined. We noted no obvious differences between the two treatment groups with respect to neurologic complications. However, we did not undertake a systematic evaluation of dosages in the treatment of AIDS dementia complex, and definitive recommendations for such treatment cannot be made on the basis of the results of this study.
Chemoprophylaxis for P. carinii pneumonia was allowed during the latter part of our study. Although the use of prophylaxis was more common in the low-dose group, its use in combination with zidovudine did not appear to bias the results of the study, and it also cannot account for the improved survival of subjects who received the lower dose. No difference in subsequent survival was noted between the subjects who received prophylaxis and those who did not. Moreover, within subgroups defined according to the use or nonuse of prophylaxis, survival continued to be better in the low-dose group. Thus, there appeared to be no increased survival benefit among subjects who received both prophylaxis and zidovudine. This may reflect the late use of prophylaxis in the study.
On the basis of our findings, a lower daily dose of zidovudine (a total daily dose of 600 mg) should be used in the treatment of patients with advanced HIV disease. An optimal dose of zidovudine for the treatment of HIV infection has not yet been determined, however. It is possible that an even lower daily dose of zidovudine will still be effective and even less toxic.
Supported by the AIDS Clinical Trials Group, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
*The following institutions and persons are members of the AIDS Clinical Trials Group or participated in this trial (a list of all contributors is available from Dr. Fischl): University of Miami School of Medicine: Raj B. Uttamchandani, M.D., Leslie Thompson, R.N., B.S.N., and Lisa Dearmas, R.N., B.S.N. Research Triangle Institute: Connie L. Hobbs, B.S., Randolph Lucas, M.S., and Barbara A. Moser, M.S. Division of AIDS, National Institute of Allergy and Infectious Diseases: Maureen Myers, Ph.D., and Judith Feinberg, M.D. Harvard Medical School: J. Davis Allan, M.D., Clyde S. Crumpacker, M.D., and Helen Fitch, R.N. University of Washington School of Medicine: Robert W. Coombs, M.D., Ph.D., Lawrence Corey, M.D., and Dana K. Cummings, A.R.N.P. University of Southern California: Fred B. Sadler, M.D., and John M. Leedom, M.D. University of Pittsburgh: John Armstrong, Sc.D., Deborah McMahon, M.D., and George J. Pazin, M.D. University of California, San Diego: Stephen A. Spector, M.D., Samuel A. Bozzette, M.D., and Joanne Santangelo, M.S.N., F.N.P. Johns Hopkins School of Medicine: Janet Horn, M.D., Kenrade E. Nelson, M.D., and Carol Hendricksen, R.N., M.Ed. Kaiser–Permanente Hospital: George Matula, M.D. Stanford University: Gulshan Bhatia, M.D. University of Rochester School of Medicine: Carol Plank, R.N., Ross G. Hewitt, M.D., and Donald Blair, M.D. Albert Einstein—Montefiore Medical Center: Roy Soeiro, M.D., Carol Harris, M.D., and Gayle Kreinik, R.N. Memorial Sloan-Kettering Cancer Center: Jill Solan, R.N., and Donald Armstrong, M.D. University of California, San Francisco—San Francisco General Hospital: John Mills, M.D., and Barbara Brodie, R.N. Tulane University Medical School: Newton E. Hyslop, M.D., and Gregory T. Valainis, M.D. Louisiana State University Medical Center: George F. Risi, M.D. University of Minnesota: Margaret Simpson, M.D., Frank S. Rhame, M.D., and Ann DePaolis-Jones, R.N., B.S.N. Mt. Sinai Medical Center: Joseph Hassett, M.D., Henry Sacks, M.D., and Donna Mild-van, M.D. University of California, Los Angeles: W. David Hardy, M.D., Ronald Mitsuyasu, M.D., and Holly Fall, R.N., N.P. Duke University Medical Center: Hetty Waskin, M.D., John A. Bartlett, M.D., and Anthony J. Adinolfi, R.N.
We are indebted to the AIDS Clinical Trials Group research staff for providing data for this study, to the subjects who volunteered to assist in this effort, to Dr. Robert Makuch for initial statistical support in the study design, and to the Burroughs Wellcome Company for the donation of study medication.
Source Information
From the University of Miami School of Medicine, Miami (M.A.F.); the Research Triangle Institute, Research Triangle Park, N.C. (C.B.P.); the Division of AIDS, National Institute of Allergy and Infectious Diseases, Rockville, Md. (C.P.); the Harvard School of Public Health, Boston (M.W., A.T.); the Harvard Medical School, Boston (M.S.H.); the University of Washington School of Medicine, Seattle (A.C.C.); the University of Southern California, Los Angeles (D.A., S.R.); the University of Pittsburgh, Pittsburgh (M.H.); the University of California, San Diego (D.D.R.); the Johns Hopkins School of Medicine, Baltimore (E.F.); Stanford University, Stanford, Calif. (T.C.M.); the University of Rochester School of Medicine, Rochester, N.Y. (R.C.R.); the Memorial Sloan-Kettering Cancer Center, New York (J.G.); the Albert Einstein—Montefiore Medical Center, Bronx, N.Y. (N.S.); and the University of California, San Francisco—San Francisco General Hospital (G.S.L.). Address reprint requests to Dr. Fischl at the University of Miami School of Medicine, Department of Medicine R-60A, P.O. Box 016960, Miami, FL 33101.
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