Original Article
Once-Daily Administration of 2′,3′-Dideoxyinosine (ddI) in Patients with the Acquired Immunodeficiency Syndrome or AIDS-Related Complex — Results of a Phase I Trial
N Engl J Med 1990; 322:1340-1345May 10, 1990
- Abstract
- Abstract
We conducted a Phase I open-label trial of 2′,3′-dideoxyinosine (ddI) for the treatment of the acquired immunodeficiency syndrome (AIDS) and severe AIDS-related complex. A single daily dose of ddI was administered orally to 34 patients (17 with AIDS and 17 with AIDS-related complex) for a median of 12 weeks (range, 2 to 56). We studied six dose levels from 1.6 to 30.4 mg per kilogram of body weight per day. Of the 17 patients previously treated with zidovudine, 13 had had hematologic side effects.
The maximal tolerated dose of oral ddI was estimated to be 20.4 mg per kilogram per day. Pancreatitis and peripheral neuropathy were the major dose-limiting toxic effects. Other toxic effects included elevations in hepatic transaminase levels, abnormalities in cardiac conduction, rash, and asymptomatic elevations in serum urate levels and the creatine kinase fraction from skeletal muscle.
Treatment with ddI was associated with an increase in the mean number of CD4 lymphocytes from 125 per cubic millimeter at base line to 182 per cubic millimeter after 10 weeks (P = 0.005). There were also increases after 12 weeks in the mean total lymphocyte count (from 0.8 to 1.2×109 per liter) and the mean hemoglobin level (from 12.9 to 14.1 g per deciliter) (both P<0.01). The amount of human immunodeficiency virus p24 antigen decreased by more than 50 percent in 14 of 19 patients with detectable antigen. No differences in response were observed between patients previously treated with zidovudine and those never treated with the drug.
We conclude that ddI has antiretroviral activity in patients with AIDS or AIDS-related complex and that the toxicity of ddI differs from that of zidovudine. However, controlled trials are necessary to evaluate the efficacy of ddI. (N Engl J Med 1990; 322:1340–5.)
Media in This Article
Table 1
Dose Levels of ddI.Table 2
Clinical and Demographic Characteristics of the 34 Patients.Article Activity
- Article
CURRENTLY, the most promising agents for the treatment of the acquired immunodeficiency syndrome (AIDS) are chemotherapeutic drugs that inhibit the human immunodeficiency virus (HIV) by targeting the RNA-dependent DNA polymerase specific to the virus.1 2 3 4 5 6 7 8 9 Among these drugs, the dideoxynucleoside analogues have been the focus of intense study in the treatment of HIV disease.1 , 6 7 8 9 The most studied drug in the class is 3′–azido-2′,3′–dideoxythymidine (zidovudine or AZT). Since its introduction, zidovudine has reduced HIV-related morbidity and mortality,10 11 12 but it has serious toxic effects,10 , 12 13 14 15 16 17 the most important being myelosuppression.10 , 12 , 13 After extended therapy, clinical deterioration occurs in most patients,18 resulting perhaps from the development of strains of HIV resistant to the drug.19 The clinical limitations of zidovudine emphasize the need for other antiretroviral therapies that are not cross-resistant.
2′,3′-dideoxyinosine (ddI) is a purine dideoxynucleoside analogue that inhibits the replication of HIV.6 Within cells, ddI is metabolized to form its active analogue, 2′,3′-dideoxyadenosine-5′–triphosphate,20 , 21 which has an intracellular half-life of more than 12 hours.22 Therefore, ddI may be clinically effective when administered on an infrequent schedule. In vitro studies show that ddI has a higher therapeutic index than other dideoxynucleoside analogues,6 , 23 with minimal toxic effects on bone marrow progenitor cells24 and in vitro activity against strains of HIV resistant to zidovudine.19 On the basis of these findings, ddI has been tested in patients with symptomatic HIV disease.25 , 26 In this report, we present the clinical and laboratory findings of a Phase I open-label, dose-finding trial involving 34 patients with AIDS or AIDS-related complex treated with ddI once daily. The data we report show that ddI can safely be given to patients with severe HIV infection, and document a toxicity profile different from that of zidovudine.
Methods
Patient Population
Thirty-four patients who received ddI are discussed in this report. All had documented HIV disease according to the criteria of the Centers for Disease Control for Group IV infection, with fewer than 400 CD4 lymphocytes per cubic millimeter. Criteria for eligibility included a hemoglobin level of at least 10 g per deciliter; a granulocyte count of at least 1000 per cubic millimeter; a platelet count of at least 80,000 per cubic millimeter; normal serum urate values and hepatic and renal function; the absence of pregnancy; the absence of therapy with antiretroviral drugs, immunomodulators, chemotherapeutic agents, or systemic antimicrobial agents within 30 days; and the absence of active use of intravenous drugs or a history of cardiac disease. All patients with CD4 lymphocyte counts below 200 per cubic millimeter at entry received Pneumocystis carinii prophylaxis with aerosolized pentamidine.27
Evaluation of Patients
Prestudy evaluations included a medical history, physical examination, and laboratory tests as detailed above. In addition, quantitative T-lymphocyte and B-lymphocyte phenotyping, the measurement of delayed cutaneous hypersensitivity reactions to the Mérieux panel, and the measurement of anti-HIV antibody and serum levels of HIV p24 antigen by enzyme-linked immunosorbent assay (Abbott Laboratories, N. Chicago)28 were performed. Subjects were evaluated twice before enrollment, daily during the first 16 days of the study, then weekly until week 10, biweekly until week 24, and monthly thereafter. Initial and steady-state serum and urine pharmacokinetic studies were also performed (data not shown).
Treatment Plan
After they had given informed consent, the patients received ddI intravenously over a one-hour period each day for 14 days. They then received ddI orally at twice the intravenous dose. Since ddI is acid labile, the oral doses were taken on an empty stomach after the ingestion of an aluminum hydroxide or magnesium hydroxide antacid. Six dose levels of ddI were studied (Table 1Table 1
Dose Levels of ddI.). The patients were assigned sequentially to one of the six levels (A through F), except for five patients assigned to level D and three assigned to level E who were treated out of sequence. No patient was treated at more than one level. Higher dose levels were initiated with the next group of patients after we had amassed at least four weeks of experience at the previous level. Treatment with ddI was interrupted for major opportunistic infections or herpetic infections that required treatment with acyclovir. Treatment with ddI was also stopped in cases of adverse reactions of moderate severity, and it was resumed at half the initial dose when the toxic effects resolved. It was discontinued in cases of severe or life-threatening toxic effects.Criteria for Response
The effects of ddI on the patients' clinical condition, immune function, and serum p24-antigen level, a surrogate marker of viral replication, were monitored. Toxicity was measured according to the World Health Organization's grading system. Clinical criteria used to assess the efficacy of ddI included weight gain, Karnofsky score, the occurrence and frequency of AIDS-related opportunistic infections, the development or progression of HIV-related neoplasms, and survival.
Statistical Analysis
Using the Statistical Analysis System (SAS, Cary, N.C.), we used a two-tailed t-test to assess differences between hematologic measures before and after treatment. The values in the patients with hematologic intolerance to zidovudine were compared with those in the other patients with use of Student's t-test. The Wilcoxon signed-rank test (two-tailed) for paired samples was used to evaluate changes in CD4 cell counts and serum levels of p24 antigen. The data were analyzed according to previous zidovudine treatment and the dose level of ddI.
Results
Patients
The demographic characteristics of the 34 patients treated in this study between September 12, 1988, and October 1, 1989, are outlined in Table 2Table 2
Clinical and Demographic Characteristics of the 34 Patients.. Twenty-four patients remain in the study, with a mean duration of treatment of 15.8 weeks (median, 12; range, 2 to 56). Reasons for withdrawal from the study have included recurrent central nervous system toxoplasmosis (one patient), the development of central nervous system lymphoma (two), adverse reaction to ddI (three), the resumption of active use of intravenous drugs (two), probable suicide (one), and the patient's request (one). Three patients have died — one of recurrent central nervous system toxoplasmosis, one of central nervous system lymphoma, and one an apparent suicide.Adverse Reactions
Data on toxicity are shown in Table 3Table 3
Probable Drug-Related Toxicity.. Overall, ddI was well tolerated at the doses discussed here. The maximal tolerated dose — defined as the maximal dose at which less than 33 percent of the patients experienced moderate (grade 3) or life-threatening (grade 4) drug-related side effects — was determined to be 20.4 mg per kilogram of body weight per day (dose level E).Pancreatitis developed in two patients receiving oral doses of 30.4 mg per kilogram per day (dose level F) after 10 and 12 weeks. In both patients the condition was characterized by nausea and vomiting, abdominal pain, and elevations in the serum amylase level. One patient had simultaneous elevations in serum transaminase levels.
A painful peripheral neuropathy of the lower extremities developed after 12 weeks in one patient treated at dose level F. He had no history of neuropathy. Neuropathic pain has slowly resolved over a period of eight weeks, but it persists.
In five patients elevations in hepatic transaminase levels required the reduction or interruption of treatment at oral doses ranging from 4.0 to 30.4 mg per kilogram per day (dose levels B through F). Liver biopsies were performed in two of these patients. One patient was found to have chronic active hepatitis and early cirrhosis. The second patient's liver biopsy was nondiagnostic. Additional liver-function abnormalities were attributed to a heavy intake of alcohol in one patient and to concomitant isoniazid therapy in two patients.
In one patient with an underlying cardiomyopathy, QT prolongation was evident on electrocardiography performed after the intravenous infusion of ddI at a dose of 2.0 mg per kilogram per day. The abnormalities in cardiac conduction resolved with the discontinuation of ddI.
Another patient receiving ddI at a dose of 4.0 mg per kilogram per day had a grade 2 rash. When the patient was rechallenged at a dose of 2.0 mg per kilogram per day, a grade 3 rash developed and ddI was discontinued.
Other minor toxic effects included constipation and an asymptomatic elevation in the serum creatine kinase fraction from muscle. Asymptomatic hyperuricemia occurred in 19 patients, and its incidence increased at the three highest dose levels.
Hematologic Studies
Comparisons of hematologic measurements are shown in Table 4Table 4
Mean Hematologic Values in the Study Patients.. Significant increases in total leukocyte and absolute lymphocyte counts as compared with values before treatment were observed after two weeks, and the increases were sustained through week 12 (P<0.01). A decrease in the hemoglobin level and hematocrit was noted after two weeks, most probably due to extensive phlebotomy. An overall increase in the hemoglobin level and hematocrit was observed after 12 weeks (P<0.01). There was no significant difference between the patients with previous hematologic intolerance to zidovudine and those who had never taken the drug.Immunologic Data
Comparisons of the absolute CD4 and CD8 lymphocyte counts are shown in Table 5Table 5
CD4 and CD8 Lymphocyte Counts in the Study Patients.*. Increases in the CD4 and CD8 lymphocyte counts were observed after two weeks of intravenous ddI. Significant increases in the CD4 lymphocyte count were sustained with oral ddI therapy through week 24. Significant increases in the CD8 lymphocyte count were seen until week 6. There were no significant differences in CD4 or CD8 lymphocyte counts between patients who received low doses of ddI (levels A to C) and those who received higher doses (levels D to F).CD4 lymphocyte counts increased by more than 50 percent of base-line values and by more than 50 cubic millimeters in 18 of 33 patients (55 percent) who completed two weeks of intravenous treatment with ddI. Among these 18 patients, increases in CD4 cell counts were sustained in 13 of the 14 (93 percent) who received oral ddI for at least six weeks.
Of the 28 patients with absolute CD4 lymphocyte counts below 200 per cubic millimeter before treatment, the count increased in 12 (43 percent) to more than 200 per cubic millimeter after two weeks of ddI therapy. The increases were sustained for six weeks or longer in 10 patients. There was no statistical difference in the elevations in the CD4 lymphocyte count between patients who had previously received zidovudine and those who had not.
Virologic Data
Comparisons of serum levels of HIV p24 antigen are shown in Table 6Table 6
Effect of ddI on Serum Levels of p24 Antigen.. Nineteen patients were seropositive for HIV p24 antigen (mean level, 292 pg per milliliter; range, 39 to 927) before the study began. In 12 patients (63 percent), there was a significant decrease in serum levels of p24 antigen after one week of therapy. After two weeks of intravenous treatment, 14 patients (74 percent) had decreases of 50 percent or more in serum p24-antigen levels. Five patients have demonstrated the sustained suppression of p24 antigen for more than six weeks. Only two patients became seronegative for p24 antigen. One patient who was p24 antigen—negative before treatment became antigenemic at dose level F. Decreases in levels of p24 antigen appear to be dose-related, but too few of our patients are seropositive at dose levels A through C to permit a statistical comparison.Clinical Status
In the 27 patients who completed at least six weeks of therapy, 23 (85 percent) reported increased levels of energy, reduced fatigue, and increased appetite. There was a mean increase in weight of 1.3 kg after six weeks (P = 0.015). Twenty-two patients (12 with AIDS and 10 with AIDS-related complex) were anergic before treatment. A delayed hypersensitivity response, defined as more than 2 mm of induration in reaction to the Mérieux panel, was observed in 8 of 15 anergic patients (53 percent) who received ddI for more than six weeks. Oral hairy leukoplakia was present in nine patients. It resolved in six patients with ddI treatment alone. Eleven patients had grade 1 peripheral neuropathy before the study. Eight patients have reported the resolution of their symptoms during ddI therapy. Paresthesias persist unchanged in three patients.
One of four patients with Kaposi's sarcoma had a regression of cutaneous lesions. Of the remaining three, two had stable disease, and one progressive disease. New Kaposi's sarcoma did not develop in any patient during the study, but two patients were given a diagnosis of central nervous system lymphoma four and five weeks after starting ddI therapy.
Two patients had major opportunistic infections during the study. One patient was given a diagnosis of P. carinii pneumonia and candida esophagitis after three weeks of treatment with ddI. A second had recurrent central nervous system toxoplasmosis after five weeks of ddI therapy. No patient treated with ddI for more than six weeks in this study has had a major opportunistic infection.
Discussion
Zidovudine has been shown to reduce the incidence of HIV-related morbidity and mortality.11 , 12 Although its clinical efficacy has been documented repeatedly, its use is frequently limited by the development of HIV resistance and toxicity.10 , 12 13 14 15 16 17 18 19 As a result, clinical trials investigating other dideoxynucleosides are in progress.
In September 1988, we initiated a dose-finding Phase I study of the efficacy and safety of ddI given once daily. In our experience with 34 patients, ddI was generally well tolerated, with acceptable toxic effects for up to 56 weeks. The toxicity profile of ddI appears to be substantially different from that of zidovudine. The maximal tolerated oral dose of ddI in our study was estimated to be 20.4 mg per kilogram per day, and the development of pancreatitis and peripheral neuropathy were the major dose-limiting toxic effects. However, the treatment of HIV disease requires extended therapy. The long-term or cumulative toxic effects that may limit the therapeutic efficacy of ddI are unknown. A study of ddI given twice daily reported painful peripheral neuropathy in 8 of 37 patients.26 The development of neuropathy in these patients was related to the total cumulative dose of ddI and to the individual daily dose. The maximal tolerated dose of ddI in that study was 12 mg per kilogram per day.26 The higher maximal tolerated dose and the lower incidence of neuropathy observed in our study suggest that toxicity may also be associated with the dose schedule.
Other toxic effects that led to the withdrawal of ddI included hepatitis, rash, and abnormalities in cardiac conduction. These effects did not appear to be dose-related. Although hyperuricemia was noted in all dose groups, the degree appeared to be dose-related. Minor toxic effects that appeared to be unrelated to dose included asymptomatic myositis and constipation.
In contrast to zidovudine, once-daily ddI did not produce myelosuppression in our patients. A significant improvement in the total leukocyte and absolute lymphocyte counts was noted after two weeks of intravenous ddI therapy. These increases were sustained when the drug was given orally. Significant increases in the hemoglobin level and hematocrit were noted after 10 weeks of treatment with ddI. These changes occurred in patients who had had hematologic intolerance to zidovudine and in patients who had not been treated with that drug.
The Phase I study of ddI presented here does not clearly demonstrate an effect on the morbidity related to severe HIV infection. After a median duration of treatment of 12 weeks, however, signs of overall clinical improvement were noted in the majority of the patients we treated. Although ddI induced a painful peripheral neuropathy in 1 patient at the highest dose level, 8 of the 11 patients with preexisting neuropathy reported a resolution of their symptoms.
This study demonstrates that ddI given once daily results in improved immunologic and virologic measures in patients with AIDS and AIDS-related complex. Increases in CD4 and CD8 lymphocyte counts and decreases in p24-antigen levels occurred after two weeks of intravenous ddI. The increases in CD4 and CD8 lymphocyte counts were sustained with oral ddI. The increases were independent of dose level or previous treatment with zidovudine. The sustained suppression of viral p24 antigen was observed in nearly half the patients who had an initial response to intravenous therapy. The improvement in immunologic and virologic measures produced by ddI administered once daily is comparable to the results reported by other investigators who administered ddI twice or thrice daily.25 , 26 The efficacy of infrequent dosing is consistent with the prolonged intracellular half-life of 2′,3′-dideoxyadenosine-5′-triphosphate, the active metabolite of ddI.
Although ddI given once daily appears to benefit patients with severe HIV infection and to have acceptable toxic effects, it is not yet clear whether extended therapy will sustain the clinical, immunologic, and virologic improvements produced by ddI. Further studies are needed to define the optimal dose and schedule of ddI and to compare its efficacy with that of zidovudine. Large multicenter, randomized, double-blind clinical trials by the AIDS Clinical Trials Group comparing ddI and zidovudine are now under way. ddI is also available through a new "parallel track" to patients who are ineligible for Clinical Trials Group trials and who are deteriorating clinically with zidovudine treatment or are intolerant to the drug. Physicians monitoring these patients must be alert to the major drug-related toxic effects of pancreatitis and neuropathy. Early recognition of the symptoms of pancreatitis and peripheral neuropathy and the immediate discontinuation of the drug are essential to preventing the progression of these painful and debilitating side effects. Until more patients are treated and comparative trials are completed, conclusions about the long-term toxicity of ddI, its effect on survival, and its role in the treatment of HIV disease cannot be drawn.
Supported in part by a General Clinical Research Center grant (00533) from the Division of Research Resources, National Institutes of Health, to the Boston University School of Medicine, and by Bristol-Myers/Squibb.
We are indebted to the staff of the Clinical Research Center of the Boston University School of Medicine, the medical house officers at Boston City Hospital, the physicians, nurses, and support staff of the Immunodeficiency Clinic at Boston City Hospital, and the referring physicians for their support of this work.
Source Information
From the Division of Hematology—Oncology and the Clinical AIDS Service, Department of Medicine, Boston City Hospital (T.P.C., L.M.K., C.A.S., H.A.L.), and the Evans Department of Clinical Research and the Department of Medicine, Boston University Medical Center (C.J.P., R.P.M.), both in Boston; and the Department of Infectious Diseases Clinical Research, Bristol-Myers Squibb Co., Wallingford, Conn. (J.K.R., C.M.). Address reprint requests to Dr. Cooley at the Division of Hematology—Oncology, Boston City Hospital, 818 Harrison Ave., Boston, MA 02118.
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