Original Article
2′,3′-Dideoxyinosine (ddI) in Patients with the Acquired Immunodeficiency Syndrome or AIDS-Related Complex — A Phase I Trial
N Engl J Med 1990; 322:1333-1340May 10, 1990
- Abstract
- Abstract
2′,3′-dideoxyinosine (ddI) is a purine analogue that after intracellular metabolic conversion suppresses the replication of the human immunodeficiency virus (HIV). We conducted a Phase I dose-escalation study of ddI in 17 patients with the acquired immunodeficiency syndrome (AIDS) and 20 patients with AIDS-related complex. The drug was administered twice daily over a dose range of 0.4 to 66 mg per kilogram of body weight per day for 2 to 44 weeks.
The maximal tolerated oral dose of ddI was estimated to be 12 mg per kilogram per day. The major dose-limiting toxic effects were a painful peripheral neuropathy (in eight patients) and pancreatitis (in five). Asymptomatic elevations of the serum aminotransferase levels (in 13 patients) and the serum urate level (in 10) were also noted, but there was no dose-related hematologic toxicity. At the maximal tolerated dose, the peak plasma levels of ddI were 6.3 to 9.6 μmol per liter 0.6 to 1 hour after oral administration; the mean plasma half-life was 1.5 hours.
The administration of ddI was associated with statistically significant decreases in serum level of p24 antigen and increases in the numbers of CD4 cells at 2, 6, 10, and 20 weeks. These changes were seen at all dose levels studied. Either a clinical improvement or a weight gain of ≥2 kg was observed in 25 of 34 patients at six weeks.
We conclude that ddI is a promising therapeutic agent in patients with AIDS or AIDS-related complex. Its efficacy is currently being evaluated in large-scale, controlled clinical trials. (N Engl J Med 1990; 322:1333–40.)
Media in This Article
Figure 1
Serum Concentrations of p24 Antigen and Circulating CD4 Lymphocyte Counts in the Study Patients during the First 10 Weeks of ddI Administration.Table 1
Characteristics of the 37 Patients in the Study.Article Activity
- Article
SEVERAL dideoxynucleoside analogues are potent inhibitors of the human immunodeficiency virus (HIV) in vitro.1 One member of this class of compounds, 2′,3′-dideoxyinosine (ddI), is a purine nucleoside analogue that has in vitro activity against HIV in both T cells2 and monocytes.3 This drug also appears to have relatively little toxicity in vitro for cells in tissue culture, including human bone marrow progenitor cells.4 The drug is converted through a complex metabolic pathway to a triphosphorylated intracellular moiety, 2′,3′-dideoxyadenosine triphosphate (ddA-TP), which preferentially inhibits HIV reverse transcriptase and suppresses HIV replication by blocking the synthesis of viral DNA.5 6 7 Unlike the triphosphates of other dideoxynucleoside analogues, such as zidovudine (formerly called azidothymidine, or AZT) or dideoxycytidine, ddA-TP has a long intracellular half-life of more than 12 hours.8
At present, zidovudine is the only antiviral drug that has been demonstrated to be effective in the treatment of HIV infection.9 , 10 However, the administration of zidovudine has been associated with severe toxicity, particularly involving the bone marrow and especially in patients with more advanced forms of HIV-associated disease.11 12 13 In addition, the beneficial effects of zidovudine in patients with the acquired immunodeficiency syndrome (AIDS) appear to wane after one year of therapy, and recently the emergence of HIV strains resistant to zidovudine has been reported in patients who have received prolonged therapy with the drug.14 Therefore, the development of additional drugs for the treatment of HIV infection is clearly needed.
Because of the high in vitro activity-to-toxicity ratio of ddI noted above, as well as a favorable toxicity profile in preclinical studies in animals15 (and Bristol-Myers Squibb: unpublished data), we carried out a Phase I dose-escalation trial to evaluate the toxicity of ddI in patients with AIDS or AIDS-related complex, define pharmacokinetic indexes for the drug, and assess its effect on circulating CD4 counts and serum concentrations of p24 antigen, which are indicators of disease activity in HIV infection.
Methods
Patient Population
The patients in the study had AIDS or AIDS-related complex as defined by the criteria of the Centers for Disease Control, were ≥18 years of age, and were free of life-threatening opportunistic infections on entry into the study. The criteria for eligibility included a CD4 lymphocyte count ≤400 per cubic millimeter, white-cell count ≥2000 per cubic millimeter, platelet count ≥80,000 per cubic millimeter, hemoglobin level ≥10 g per deciliter, serum creatinine level ≤115 μmol per liter, serum uric acid level ≤0.45 mmol per liter, serum bilirubin level ≤26 μmol per liter, and hepatic-enzyme levels ≤3 times normal. The criteria for exclusion included pregnancy, seizure disorders, cardiac disease, active alcohol or drug abuse, intractable diarrhea, and the administration of antiretroviral or cytotoxic drugs within one month of entry into the study.
Dosage Regimen of ddI
The drug was administered intravenously every 12 hours for the first two weeks and then orally at twice the intravenous dose every 12 hours. Nine different dose levels of ddI were studied sequentially. After ≥4 weeks of experience at one dose level in one group of patients, treatment at the next higher dose level was begun in the next group. After the patients had received ddI treatment for 10 weeks at the initial dose level, higher doses of ddI could be administered if no toxicity had been noted. The drug was administered on an empty stomach, either with citrate phosphate buffer (for dose levels 1 to 3) or after the administration of an antacid (for dose levels 4 to 9).
Evaluation of Patients
Before enrollment, the patients had a physical examination; chest radiography; electrocardiography; a complete blood count; measurements of serum levels of bilirubin, hepatic enzymes, creatinine, and uric acid; and urinalysis. They were evaluated daily for the first two weeks of the study, weekly for the next eight weeks, and every two to four weeks thereafter, at which times the above studies were repeated. The serum triglyceride, amylase, and Upase levels were also measured routinely after cases of pancreatitis were recognized. Echocardiography was performed before entry into the study and at weeks 6 and 10 in eight patients treated at dose levels 5 to 9.
Lymphocyte subsets were counted by a FacScan flow cytometer (Becton Dickinson, San Jose, Calif.) before entry, at two weeks, and monthly thereafter. Serum p24 antigen was measured (Abbott enzyme immunoassay, Abbott Laboratories, N. Chicago) before entry, weekly for the first six weeks, biweekly for the next four weeks, and monthly thereafter. Peripheral-blood mononuclear cells were cultured for HIV before entry, at weeks 6 and 10, and every 12 weeks thereafter, by techniques described elsewhere.16 , 17
Pharmacokinetic Studies
Pharmacokinetic studies were performed after the first and last intravenous doses of ddI (on days 1 and 14) and twice after the first oral dose (on days 16 and 43). Additional plasma samples were obtained before the morning dose on days 4, 7, 10, 23, 30, and 37 to determine the steady-state levels of ddI. The samples were analyzed for ddI content by high-performance liquid chromatography with use of an assay previously validated by Bristol-Myers Laboratories (Bristol-Myers Squibb: unpublished data).
Dosage Reduction
When there were severe reactions (grade 3 of the AIDS Clinical Trials Group criteria), the administration of ddI was interrupted and was reinstituted at half the previous dose once the toxicity resolved. If grade 3 toxicity recurred or if life-threatening (grade 4) toxicity developed, the administration of the drug was discontinued permanently.
Study Sites
The studies were carried out as part of the AIDS Clinical Trials Group program of the National Institute of Allergy and Infectious Diseases at the Clinical Research Center and AIDS Center of the University of Rochester Medical Center, and at New York University at Bellevue Hospital. All the studies were approved by the institutional review boards of the respective institutions and were carried out according to the guidelines of the Department of Health and Human Services. All patients signed informed-consent forms before entry into the study.
Statistical Analysis
The data were analyzed by paired-sample t-tests (two-tailed) to compare the means, and by chi-square tests to compare the rates of events.
Results
Patient Population
Thirty-seven patients were enrolled in this study, and their characteristics are shown in Table 1Table 1
Characteristics of the 37 Patients in the Study.. Thirty patients had previously received zidovudine for a mean of 8 months (range, 2 to 21). Twenty-five of the 30 had discontinued zidovudine because of intolerance, primarily involving hematologic toxicity (Table 1). Thirty of the 37 were receiving prophylaxis for pneumocystis pneumonia, most commonly aerosolized pentamidine. All 37 patients completed at least two weeks of intravenous therapy and were followed for at least 10 weeks. The mean duration of ddI administration in the study was 17 weeks (range, 2 to 44), and the mean cumulative dose was 1.9 g per kilogram.Pharmacokinetic Indexes
After the intravenous infusion, mean peak plasma ddI concentrations of 1.2 to 76.3 μmol per liter were detected (Table 2Table 2
Peak Plasma Concentrations Obtained after Intravenous or Oral Administration of ddI.). A mean plasma half-life of 1.3 hours was noted (range, 0.9 to 1.7), and the plasma ddI concentration declined in a biexponential fashion without evidence of drug accumulation. After oral administration of ddI, peak plasma concentrations of the drug ranged from 1.0 to 29.8 μmol per liter, with a time to maximal concentration of 0.6 to 1.0 hour. The mean half-life of ddI after oral administration was 1.5 hours (range, 0.8 to 2.7), without drug accumulation. The mean bioavailability of ddI on day 16 in the patients receiving doses of 0.8 to 10.2 mg per kilogram was 0.40±0.18, and in those receiving doses of 15.2 to 33.0 mg per kilogram it was 0.23±0.09. The bioavailabilities of ddI determined on days 16 and 43 were similar.Intravenous Administration
Intravenous administration of ddI was generally well tolerated in all 37 subjects. Three subjects had mild phlebitis that resolved when the drug was administered in a more dilute solution (i.e., in a total volume of 200 ml). Two subjects had mild maculopapular rashes that did not require discontinuation of the drug and that resolved spontaneously. One subject reported palpitations with the administration of ddI but had no electrocardiographic changes. Transient mild headaches during the intravenous infusion were also occasionally reported. No adverse effects on laboratory measurements were observed during the two-week period of intravenous infusion.
Oral Administration
The major clinical adverse effects encountered were a painful neuropathic syndrome in eight patients and pancreatitis in five (Table 3Table 3
Incidence of Neuropathy or Pancreatitis in the Study Patients, According to the Oral Dose of ddI.). The neuropathic syndrome consisted of a tingling, burning, or aching in the lower extremities, particularly in the soles of the feet. The pain was particularly prominent at night but was also present throughout the day. Initially, the discomfort was noted in walking, but in more advanced cases pain interfered with sleep and routine daily activities. Examination of the lower extremities was unremarkable, except for occasional diminished vibratory sensation and decreased ankle reflexes. The results of nerve-conduction studies in six patients were normal. Neuropathy occurred in 1 of 15 patients who received mean daily doses of ≤12 mg per kilogram per day, as compared with 7 of 22 who received mean daily doses of more than 12 mg per kilogram per day (P = 0.065). Similarly, neuropathy developed in 7 of 19 patients who received total doses of more than 2 g per kilogram, but in only 1 of 18 patients who received total doses of less than 2 g per kilogram (P = 0.02). Thus, there was a trend toward an association of neuropathy with increasing daily doses of ddI, as well as with the total dose of the drug administered. The onset of neuropathy occurred from 55 to 201 days after the initiation of therapy. At the lower mean daily doses of ddI (11.5 and 16.0 mg per kilogram per day), neuropathy did not develop until days 201 and 151 of therapy, respectively. The neuropathic symptoms gradually resolved or substantially subsided over a period of four to eight weeks in seven of eight patients but remained unchanged in one patient. Three of eight patients whose neuropathy resolved were rechallenged with ddI at doses of 10 mg per kilogram per day, and no recurrence of symptoms was observed after a follow-up period of 4 to 12 weeks.Pancreatitis developed in five patients during the study, as manifested by abdominal pain and elevated amylase levels (Table 3). The episodes began with vague abdominal pain, nausea, and vomiting and progressed to moderate or severe epigastric pain, which required narcotic analgesics in three of the five patients. The peak serum amylase values ranged from 195 to 597 IU per liter, and the peak serum lipase values ranged from 626 to 2000 IU per liter. Three of the five patients required hospitalization, and the two others were treated as outpatients. The symptoms resolved within one to three weeks after the cessation of ddI therapy. The development of pancreatitis was less clearly related to the dose of ddI than was the development of peripheral neuropathy (Table 3). However, four of the five patients with pancreatitis had received mean daily doses of 19.3 mg per kilogram or more. One of the patients in whom pancreatitis developed was rechallenged with ddI at the same dose (12 mg per kilogram per day); after 12 weeks of therapy, pancreatitis developed again. Another patient was rechallenged at a lower dose and had an asymptomatic increase in the serum amylase level but no abdominal pain. Two other patients with ddI-associated pancreatitis were rechallenged at doses of 10 and 12 mg per kilogram per day and remain asymptomatic after a follow-up period of 2 to 10 weeks. In three of the patients in whom pancreatitis eventually developed, slight elevations of serum aminotransferases and alkaline phosphatase were noted before the development of symptoms, and in one patient hypertriglyceridemia was noted before the development of clinical pancreatitis. Six of 33 patients had laboratory evidence of possible low-level (grade 2) pancreatic dysfunction during the study, without clinical pancreatitis: three had elevations of serum amylase, and three had elevations of serum triglycerides.
Evidence of myocardial dysfunction or arrhythmias was not noted during the study, and serial electrocardiograms and echocardiograms were unchanged in all patients.
Laboratory Abnormalities
The laboratory abnormality that was most clearly related to the dose of ddI was asymptomatic hyperuricemia (blood uric acid levels ranging from 0.56 to 0.83 mmol per liter [9.5 to 14.0 mg per deciliter]), which was noted in 10 patients, all of whom had received ≥30 mg of ddI per kilogram per day. The uric acid levels fell to within normal limits with hydration and reduction of the ddI dose.
Elevated levels of liver enzymes, primarily the serum aminotransferases, were noted in 13 patients. In six of these, aminotransferase levels rose to more than five times normal (during weeks 8 to 19) and returned to normal after the cessation of ddI therapy. Four of these six patients were receiving doses ≥20 mg per kilogram per day, and two were receiving ≤12 mg per kilogram per day. Three of these six patients were rechallenged with ddI, and two tolerated the same dose of ddI without abnormalities in liver function, whereas one had elevated levels of liver enzymes.
No dose-related toxicity of ddI was noted on the hematologic laboratory indexes. As compared with the values on entry, the white-cell, neutrophil, lymphocyte, and platelet counts, as well as the hemoglobin level, actually rose to significantly higher levels during the first 10 weeks of the study (Table 4Table 4
Hematologic Laboratory Values during the Administration of ddI.*). Thrombocytopenia developed in three patients while they were receiving ddI: one at an oral dose of 1.6 mg per kilogram per day, one at 7 mg per kilogram per day, and the other at 66 mg per kilogram per day. In two of these, thrombocytopenia resolved with the discontinuation of ddI therapy, but in the other it did not. One patient who had previously required weekly intravenous immunoglobulin for thrombocytopenia maintained an adequate platelet count during ddI therapy without intravenous immunoglobulin for more than three months.Determination of Maximal Tolerated Dose
The adverse effects that were believed to be potentially related to the dose of ddI and that reached levels of grade 3 or 4 toxicity are shown according to dose level in Table 5Table 5
Adverse Effects Potentially Related to Increasing Doses of ddI.. When maximal tolerated dose was defined as the maximal dose at which no more than 33 percent of the subjects had grade 3 or 4 dose-related toxic effects, the maximal tolerated dose of ddI for the period of study was 12 mg per kilogram per day. Neuropathy or pancreatitis developed in 10 of 22 patients (45 percent) who received doses of ddI above the maximal tolerated dose, as compared with 2 of 15 patients (13 percent) who received doses ≤12 mg per kilogram per day.Effects on Serum Levels of p24 Antigen and HIV Cultures
Seventeen patients had serum levels of p24 antigen above 40 pg per milliliter on entry into the study (mean, 235 pg per milliliter; range, 42 to 598). As shown in Figure 1Figure 1
Serum Concentrations of p24 Antigen and Circulating CD4 Lymphocyte Counts in the Study Patients during the First 10 Weeks of ddI Administration., reductions in p24-antigen concentrations were seen at each dose level studied, so that no relation between the dose of ddI and reduction of the p24 level was observed. When the results at all doses were analyzed in the aggregate (Table 6Table 6
Serum Concentrations of p24 Antigen during ddI Administration.), statistically significant decreases in levels of p24 antigen were noted at 2, 6, 10, and 20 weeks of therapy, as compared with the values obtained on entry. The p24-antigen levels remained decreased at weeks 30 and 40 in the only p24-positive patient who was treated for that length of time. No patients who were seronegative for p24 antigen on entry became seropositive during the study.All 37 patients had cultures positive for HIV from peripheral-blood mononuclear samples before the study, and these remained positive throughout the study.
Effects on CD4 and CD8 Lymphocyte Counts
Increased CD4 counts were observed in at least one patient at each dose level through the first 10 weeks of ddI administration, as shown in Figure 1. When the results from all the patients receiving ddI were analyzed in the aggregate, the mean CD4-cell counts were significantly higher at weeks 2, 6, 10, and 20 than at base line (Table 7Table 7
Circulating CD4 and CD8 Lymphocyte Counts during ddI Administration.*). Increases in CD4 counts ≥40 cells per cubic millimeter were seen at weeks 20, 30, and 40, in 6 of 13, 2 of 6, and 1 of 2 patients, respectively. Increases in CD8 counts were also observed (Table 7), and the counts became significantly higher at weeks 2 and 6 of the study, with a trend toward higher values at week 10.Outcome of Patients in the Study
Five patients enrolled in the study have died: one with cytomegalovirus (at 26 weeks), one with Pneumocystis carinii pneumonia (at 2 weeks), and one with cryptococcosis and toxoplasmosis (at 15 weeks). A fourth patient died with central nervous system dementia (at 20 weeks), and a fifth died of a progressive wasting syndrome (at 36 weeks). In addition to the above, four patients had opportunistic infections during the study (two with P. carinii at weeks 10 and 12, one with cytomegalovirus at week 3, and one with Toxoplasma gondii at week 6). One patient with cutaneous Kaposi's sarcoma had Kaposi's sarcoma in the lung diagnosed at week 14.
Clinical Response
We examined the overall clinical response of the subjects after six weeks of ddI therapy. Of the 34 patients who completed six weeks of treatment, 17 (50 percent) reported an increase in energy or in their sense of well-being. Seventeen of the 34 patients had weight gains of at least 2 kg during this time. Nine of the 34 had both symptomatic improvement and a weight gain of ≥2 kg at the end of this initial six-week study period. Either a weight gain or a clinical response was seen in 25 of the 34 patients (74 percent), no change in clinical status in 6, and a worsening in 3. No dose-related effect of ddI on clinical status could be ascertained from the study.
Discussion
We conducted a Phase I study of ddI in 37 patients with AIDS or AIDS-related complex who received ddI for a mean of 17 weeks. The maximal tolerated dose of the drug was estimated as 12 mg per kilogram per day. The dose-limiting toxic effects included a painful neuropathic syndrome involving the lower extremities and acute pancreatitis. The neuropathic syndrome appeared to be related to both the daily and the total doses of ddI. The pathogenesis of the neuropathic syndrome is unknown, but the clinical manifestations are similar to those observed with other dideoxynucleosides, and particularly with dideoxycytidine.18 , 19 On withdrawal of the drug, the neuropathic symptoms substantially cleared or resolved in seven of eight subjects within four to eight weeks, and three of these subjects tolerated lower doses of ddI (750 mg per day).
The relation of pancreatitis to an increasing dose of ddI was less clear than that of neuropathy. Four of the five patients with pancreatitis were eventually rechallenged with the same dose of ddI or a lower one, and two of these have tolerated the lower dose without any evidence of pancreatic dysfunction. The mechanism of the apparent association between ddI and pancreatitis is also unknown. The patients in the study reported no alcohol abuse, and none were receiving medications known to cause pancreatitis. However, three of five subjects in whom pancreatitis developed received prophylaxis with aerosolized pentamidine, and a case of pancreatitis that was possibly attributable to treatment with aerosolized pentamidine has recently been reported.20 It has also been reported recently that pancreatic lesions may frequently be found at autopsy in patients with AIDS, although clinical evidence of pancreatitis is much less common.21 It is possible that ddI treatment may exacerbate the underlying subclinical pancreatitis in this group of patients.
The only other toxic effect observed in this study that was clearly dose-related was hyperuricemia, which was seen exclusively at doses ≥30 mg per kilogram per day, and which probably reflects a metabolic degradation of ddI through purine catabolic pathways. Elevated levels of aminotransferases were observed sporadically throughout the study and resulted in an interruption of the administration of ddI in six patients, four of whom were receiving doses above the maximal tolerated dose. In our study the absence of dose-related hematologic toxic effects was particularly noteworthy, even in patients who had previously been intolerant to zidovudine because of anemia or neutropenia. In fact, a moderate improvement in hematologic laboratory values was noted during the study, suggesting that ddI may partly reverse or ameliorate hematologic suppression in these patients.
The administration of ddI was also associated with improvement in certain markers of HIV disease activity — namely, statistically significant decreases in concentrations of p24 antigen and increases in CD4 counts. These changes were observed over the entire dose range of the study, including the lowest dose level studied, so that a dose-related effect of ddI on p24-antigen levels or CD4 counts could not be ascertained. The potentially beneficial effects on p24 levels and CD4 counts in this study were obtained when ddI was administered infrequently (every 12 hours) and at some doses that resulted in relatively low plasma concentrations of drug. As has been reported previously,22 our pharmacokinetic studies noted that ddI has a short plasma half-life (mean, 1.5 hours) and does not accumulate in plasma. The prolonged intracellular half-life of ddA-TP, the active moiety of ddI, may account for the apparent effects of ddI observed with this dosage regimen.
The interpretation of the potential clinical benefits of ddI is limited by the experimental design of this Phase I uncontrolled study. Nonetheless, improvements in a sense of well-being or small weight gains were observed in approximately three fourths of the patients after six weeks of ddI therapy. Thus, our observations are consistent with those reported earlier by Yarchoan et al., which suggested that ddI might be useful in the therapy of patients with AIDS or AIDS-related complex.22 In that report, no maximal tolerated dose was reached, but those investigators have subsequently encountered dose-limiting toxic effects similar to those that we have reported (Yarchoan R: personal communication). Our studies also indicate that doses below the maximal tolerated dose appeared to be tolerated well when administered for prolonged periods, including periods as long as 6 to 11 months. Potentially beneficial effects on the surrogate markers of HIV infection were also noted at doses as much as eight times lower than the maximal tolerated dose.
The clinical efficacy of ddI can be established only by large-scale, rigorously controlled clinical trials. Such trials, which have begun under the auspices of the AIDS Clinical Trials Group program of the National Institute of Allergy and Infectious Diseases, will compare ddI and zidovudine with respect to efficacy and toxicity in patients with AIDS or advanced AIDS-related complex, as well as evaluate ddI treatment in a larger number of patients who have had hematologic toxicity with zidovudine. On the basis of the Phase I data described above, the doses of ddI selected for the comparison trials range from 350 to 750 mg per day, given every 12 hours. In comparison with zidovudine, ddI may offer several potential advantages, including less frequent administration, the absence of hematopoietic toxicity, and in vitro activity against HIV strains resistant to zidovudine.14
Physicians who administer ddI to patients should be alert for toxic effects, in particular the neuropathic syndrome and pancreatitis. Patients should be monitored carefully for the earliest signs of these or other, hitherto unrecognized toxic effects, particularly when the drug is administered for longer periods than in our study. When such toxic effects are encountered, prompt discontinuation of the drug is essential to avoid possible irreversible injury.
Supported by research project cooperative agreements (5U01 AI27658 and 5U01 AI27665) from the National Institute of Allergy and Infectious Diseases, and a Clinical Research Center grant (RR00044) from the Division of Research Resources, National Institutes of Health, Bethesda, Md.
Source Information
From the Infectious Diseases Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, N.Y. (J.S.L., R.C.R., C.S.P., R.D.); the Department of Medicine, New York University School of Medicine, New York (M.S., M.L., F.T.V.); the Department of Pharmacy and Medicine, State University of New York at Buffalo, Buffalo, N.Y. (G.D.M.); the Metabolism and Pharmacokinetics Department (C.K., Syracuse, N.Y.) and the Infectious Diseases Division (C.McL.), Bristol-Myers Squibb Co., Walling-ford, Conn.; and the AIDS Program, National Institute of Allergy and Infectious Diseases, Bethesda, Md. (C.P.). Address reprint requests to Dr. Lambert at the Infectious Diseases Unit, University of Rochester School of Medicine and Dentistry, Box 689, 601 Elmwood Ave., Rochester, NY 14642.
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