Original Article
Dideoxyinosine in Children with Symptomatic Human Immunodeficiency Virus Infection
N Engl J Med 1991; 324:137-144January 17, 1991
- Abstract
- Abstract
Background.
2′,3′-Dideoxyinosine (ddI) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddI showed evidence of antiretroviral activity with little hematologic toxicity.
Methods.
We conducted a phase I–II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddI was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddI: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity.
Results.
After oral administration, ddI was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddI at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218×109 per liter (218 per cubic millimeter) at base line to 0.327×109 per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1×109 per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddI correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine.
Conclusions.
Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddI indicates that bioavailability is an important consideration in the use of ddI to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity. (N Engl J Med 1991; 324:137–44.)
Media in This Article
Figure 1
Effect of ddI on Surrogate Markers of HIV Infection.Table 1
Characteristics of Patients at Entry.*Article Activity
- Article
THE growing number of children infected with the human immunodeficiency virus (HIV) makes it imperative that pediatricians rapidly evaluate all potentially useful antiretroviral agents. Zidovudine (formerly azidothymidine, or AZT) decreases morbidity and mortality from HIV infection in adults and children.1 2 3 4 However, the benefits of zidovudine can be limited by intolerance and toxicity (particularly myelosuppression)1 , 5 , 6 and by refractory disease.7 Recent studies suggest that dideoxyinosine (ddI), an agent that induces less myelosuppression than zidovudine, may have an important role in the treatment of patients in whom the disease is refractory to zidovudine therapy or who have intolerance to zidovudine and that it may be a less toxic alternative for initial therapy.8 9 10 11 12 13 In January 1989, to determine the safety of ddI in children and their degree of tolerance of the drug, we began a phase I–II trial of ddI in children with symptomatic HIV infection. We evaluated the use of ddI both in children who had never received antiretroviral agents and in those who had intolerance to zidovudine or in whom the disease was refractory to zidovudine treatment.
Methods
Patients
Patients 3 months to 18 years of age with either vertical (perinatal) or blood-product transmission of HIV and class P-2 symptomatic infection (according to the criteria of the Centers for Disease Control [CDC]14) were eligible. Patients had to be free of active opportunistic infection requiring specific therapy, to have informed consent signed by a parent or guardian, and to have a total white-cell count of at least 1.2×109 per liter, an absolute neutrophil count of at least 0.75×109 per liter, a hemoglobin level of at least 95 g per liter, a platelet count of at least 50×109 per liter, serum creatinine and bilirubin levels less than three times the normal values, and liver aminotransferase levels less than five times the normal level. Patients were considered to have intolerance to zidovudine if they had had recurrent neutropenia (absolute neutrophil count, <0.5×109 per liter) or if they had required frequent blood transfusions despite a 30 percent reduction in their drug dose or could no longer continue therapy because of toxicity. Children were considered to have disease that was refractory to treatment with zidovudine if they had new or continued symptoms of HIV infection as indicated by progressive neurologic impairment, a continued weight loss of more than 10 percent, or severe recurrent opportunistic infections. Patients were not considered to have refractory disease on the basis of declining CD4 counts alone.
Study Design
The study, approved by the National Cancer Institute's Human Experimentation Review Board, was designed to evaluate the use of five dosages of ddI (60, 120, 180, 360, and 540 mg per square meter of body-surface area per day) given orally in three divided doses for a minimum of 24 weeks. Children were stratified according to previous antiretroviral therapy. A minimum of three previously untreated children and three who had refractory disease or were intolerant to zidovudine were entered into each dose cohort. Dose escalations continued unless toxicity was encountered in four of six patients at a given dose level. It was decided at the outset, however, that if serious toxic effects were discovered among adult recipients of ddI, dose escalations in this study beyond the level anticipated to produce toxic effects would not necessarily continue.
Clinical and Laboratory Monitoring
Vital signs were monitored during the initial 48 hours of the study, and patients younger than two years of age were hospitalized to begin therapy. Patients were seen weekly during weeks 2 through 6, during weeks 8, 10, and 12, and every four weeks thereafter. The complete blood count, coagulation profile, and results of the routine biochemical determinations and urinalysis were monitored throughout the study period. When pancreatitis was observed in adults as a side effect of ddI,11 serum amylase, triglyceride, and lipase levels were also measured at each visit. T-cell—subset counts, quantitative immunoglobulin assays, and p24 antigen measurements were performed at entry and monthly thereafter. HIV serologic status was assessed at three-month intervals. Chest radiography and CT and magnetic resonance imaging (MRI) scanning of the head were performed at entry and at weeks 12 and 24. Electrocardiography was performed daily during the first 3 days of ddI administration and every 12 weeks thereafter. An echocardiogram was also obtained at base line and at 24 weeks. Detailed age-appropriate neuropsychological assessment was carried out at enrollment, as previously reported.1 , 15 An abbreviated battery of tests was given for monitoring purposes at the 12-week evaluation; the complete battery was readministered only at 24 weeks in order to minimize practice effects. Children were defined as having encephalopathy at entry if there was loss or marked impairment in cognitive ability, a history of regression from or delayed achievement of developmental milestones, or both. An abnormality on CT or MRI scanning of the head was not a prerequisite for the diagnosis of encephalopathy, and an abnormal brain scan was not sufficient for a diagnosis of encephalopathy.
Drug Dosage and Delivery and Pharmacokinetic Sampling
This study was carried out under the investigational-new-drug application of the Cancer Treatment Evaluation Program (CTEP). The ddI, manufactured by Ben Venue Laboratories (Bedford, Ohio) was supplied as a sterile, freeze-dried powder and was reconstituted with 0.9 percent sodium chloride to a solution containing 64 mmol of ddI per liter (15 mg per milliliter). Up to a seven-day supply was maintained at 4°C until use. Because ddI is acid-labile, oral doses were given two minutes after the ingestion of 10 to 15 ml of magnesia and alumina (Maalox) or 15 to 20 ml of an aluminum hydroxide suspension, one-half hour before or one hour after meals. Each family received instruction on the preparation and administration of the drug. To determine single-dose pharmacokinetics, the initial dose (day 0) was administered as a one-hour intravenous infusion in 50 ml of 0.9 percent sodium chloride. Plasma samples were collected before infusion, at the end of the infusion, and 1/2, 1, 2, 3, 4, 5, and 7 hours after the infusion. Beginning on day 1, the same dose and formulation as was delivered intravenously was administered orally every eight hours. Plasma samples were obtained before the first oral dose and 1/2, 1, 1 1/2, 2, 3, 4, 5, 6, and 8 hours thereafter. The plasma concentration of ddI was measured with reverse-phase high-performance liquid chromatography.16 Compliance was monitored by vial count and by questioning the parents at each return visit.
Treatment was modified if there was evidence of severe bone marrow suppression on two or more occasions, more than 24 hours apart, that was possibly related to ddI. Clinical pancreatitis, as indicated by abdominal pain and nausea, together with a corresponding increase in serum amylase levels, also resulted in a modification of therapy. Asymptomatic hyperamylasemia was not a criterion for modification of the dose of ddI. Evidence of progressive peripheral neuropathy, or other evidence of severe toxicity that might be related to ddI, resulted in the discontinuation of the drug.
Criteria for a Response to Treatment
The patients were monitored on at least a monthly basis, with more detailed evaluations at base line and 12 and 24 weeks. Indicators of a response to treatment included a gain of at least 10 percent of the base-line weight, a reduction in the number of enlarged nodes and a decrease of 1 cm or more in the maximal size of the nodes in patients with lymphadenopathy at entry (n = 16), and a decrease of 1 cm or more in the size of the liver and spleen in patients with hepatosplenomegaly (n = 24). An immunologic response was defined as an increase of more than 10 percent in the base-line CD4 cell count (minimal increase, 50 cells), the ratio of CD4 to CD8 cells (minimal increase, 0.1), or the immunoglobulin level. A virologic response was defined as a decrease in the level of p24 antigen from more than 100 pg per milliliter at enrollment to no more than 50 pg per milliliter at each of the final two evaluations. In addition, the median CD4 count and p24 antigen level of patients with paired samples — one obtained at base line and one after 20 or 24 weeks of ddI treatment — were compared. For a neuropsychometric response, an increment of more than 10 percent in the base-line full-scale IQ score and at least 8 IQ points was required, because changes of this magnitude are unlikely to be due to practice effects. 15
Statistical Analysis
The effect of the dose of ddI and base-line clinical values on changes in the surrogate markers of viral activity over the study period were assessed with use of Fisher's exact test. The effect of ddI on CD4 counts was analyzed with the use of paired-sample t-tests to compare the median values before and after therapy, and the impact on the p24 antigen level was analyzed with the Wilcoxon signed-rank test. The correlation between the proportion of children with a decline in the p24 antigen level and the ddI dose level (expressed as a rank) was tested with the stratified MantelHaenszel test, with on-study patients (those who completed 24 weeks of ddI) and off-study patients (those who did not complete the full 24-week course) making up two strata. The relation between the plasma concentration of ddI and the decline in the p24 antigen level was analyzed with the Mann—Whitney test. All the P values reported are two-tailed. Changes in psychometric scores and group differences in these measures were evaluated with repeated-measures analysis of variance.
Results
From January to October 1989, 43 children with symptomatic HIV infection (27 previously untreated and 16 with refractory disease or intolerance to zidovudine) were enrolled in our study. The characteristics of the patients are summarized in Table 1Table 1
Characteristics of Patients at Entry.*. Of 43 patients, 8 (19 percent) did not complete 24 weeks of therapy with ddI; 6 of these children died during the 24-week period, 1 was withdrawn when pancreatitis developed after 12 weeks, and 1, with disease refractory to zidovudine, was withdrawn from the study because the disease progressed despite the oral and intravenous administration of ddI. None of the deaths were considered directly attributable to ddI (Table 2Table 2
Characteristics of Children Who Died while Receiving Dideoxyinosine (ddI).*).Pharmacokinetic Evaluation
Plasma samples were drawn from 23 children after an intravenous dose of ddI: 3 receiving 20 mg per square meter, 6 receiving 40 mg per square meter, 4 receiving 60 mg per square meter, 5 receiving 120 mg per square meter, and 5 receiving 180 mg per square meter. The peak concentration (at the end of the one-hour infusion) and the area under the plasma concentration—time curve (AUC) increased proportionally with the dose. The mean peak concentrations of ddI ranged from 3.1 μmol per liter at the dose of 20 mg per square meter to 22 μmol per liter at 180 mg per square meter, and the mean AUC ranged from 3.4 to 32 μmol · hour per liter. The half-life of ddI after the intravenous infusion was 0.8±0.4 hour, and the total body clearance was 490±190 ml per minute per square meter. Thirty-four children were monitored after their first oral dose of ddI: six receiving 20 mg per square meter, six receiving 40 mg per square meter, six receiving 60 mg per square meter, nine receiving 120 mg per square meter, and seven receiving 180 mg per square meter. Orally administered ddI was absorbed rapidly, with peak levels occurring at 30 minutes in most patients. The plasma concentrations after oral administration were lower than after the same intravenous dose (the AUC ranged from <0.2 to 13.4 μmol · hour per liter). Overall, the fraction of the oral dose absorbed (in 22 patients) was 21 percent (range, <5 to 89), and in two patients (one who received 40 mg per square meter and one 60 mg per square meter) ddI was not detected in the plasma at any time after the oral dose. As with the intravenous dose, the peak ddI concentrations and the AUC increased proportionally with the oral dose of ddI, but there was more variation in these values at each dose level when the drug was administered orally than when it was administered intravenously. The mean peak plasma concentrations ranged from 0.45 μmol per liter at the lowest dose to 4.1 μmol per liter at the highest.
Toxicity
Clinical Indexes
Two patients, one receiving 360 mg of ddI per square meter per day and one receiving 540 mg per square meter per day (10.7 and 16.2 mg per kilogram of body weight per day), were given a diagnosis of pancreatitis after 12 and 14 weeks of therapy, respectively. In each patient, the serum amylase levels had been normal two weeks earlier. The discontinuation of ddI was followed by prompt resolution of pancreatitis in both cases. In one child, ddI therapy was reinstituted at a lower dose (180 mg per square meter per day) and later increased to 270 mg per square meter per day with no recurrence of symptoms during the subsequent 51 weeks. Nonspecific abdominal pain occurred in one patient with active cytomegalovirus retinitis. It was not affected by the temporary interruption of ddI therapy but resolved during continued treatment, which coincided with the elimination of caffeine from the patient's diet. Peripheral neuropathy was not observed in any patient during the study. Diarrhea was attributed to magnesia and alumina (Maalox) in some patients and resolved after a change to aluminum hydroxide.
Laboratory Indexes
Twenty-seven patients had a hemoglobin level of less than 95 g per liter on at least one occasion during the study. These low values were obtained mainly during the first weeks of study and were probably related to the frequency of phlebotomy during this period. The hemoglobin level decreased to less than 80 g per liter in six patients (14 percent). In four of the six this decline was clearly related to intercurrent infections, but in two patients no clear cause was identified (Table 3Table 3
Hematologic Toxicity in Recipients of ddI.). Eight patients had thrombocytopenia at some time during the study; five of them had a history of thrombocytopenia. Two patients had a self-limited, transient decrease in the platelet count; and in another patient, severe thrombocytopenia, a manifestation of infection-related disseminated intravascular coagulation, resulted in the temporary discontinuation of ddI (Table 3). Although five episodes of neutropenia were documented, none was felt to be related to ddI (Table 3).Four of 32 patients who had normal serum amylase levels during the first week of ddI treatment (13 percent) had increases to more than twice the normal value (>186 U per liter) during continued therapy. Two of these four patients had pancreatitis, with dramatic increases from 74 to 700 U per liter and from 39 to 848 U per liter, respectively. However, asymptomatic hyperamylasemia (amylase level, >93 U per liter) was noted on at least one occasion in 15 patients (35 percent), and amylase levels were persistently elevated, rising as high as 488 U per liter in six patients. In three of these six patients, hyperamylasemia antedated therapy with ddI, and in the three other patients, although an amylase level was not obtained before therapy, elevation was documented during the first week of therapy. Serum lipase and triglyceride levels were not part of the initial routine monitoring. However, 18 of the 21 patients receiving the two highest doses of ddI had serum triglycerides measured on one or more occasions (mean, two per patient). The level was elevated (>1.7 mmol per liter) on at least one occasion in 13 of these 18 patients (72 percent). Sixteen of the 21 patients receiving the two highest doses had serum lipase levels assessed during therapy. Asymptomatic elevation in the lipase level (>320 U per liter) was identified in three patients. In one patient, these levels peaked at 3948 U per liter, at which time the amylase levels were normal and the serum triglyceride levels were three times the normal value.
Nine patients had normal liver aminotransferase values (alanine aminotransferase, <44 U per liter; aspartate aminotransferase, <35 U per liter) at entry. Fourteen patients, each with a history of hepatitis, had values more than three times normal. Eleven patients, all of whom had elevated base-line levels, had increases in alanine aminotransferase, aspartate aminotransferase, or both to three times the upper limit of normal or higher values. These increases were generally transient, were not associated with elevated serum bilirubin levels, and did not result in the discontinuation of ddI treatment. Seven of 14 patients with alanine aminotransferase levels, aspartate aminotransferase levels, or both at least three times higher than normal at the time of enrollment had a reduction of 50 percent or more in these values while receiving ddI. Fourteen patients had an increase in either the blood urea nitrogen level (n = 9), the serum creatinine level (n = 3), or both (n = 2) during therapy. In 10 of these patients the increases were transient and mild, with a peak blood urea nitrogen level of less than 8.9 mmol per liter (<25 mg per deciliter) and peak serum creatinine levels below 88 mmol per liter (<1.0 mg per deciliter). In the remaining four patients, none of whom completed the 24 weeks of therapy, these abnormalities were caused by a number of factors. Ten of the 42 patients evaluated had an asymptomatic elevation in the serum uric acid level to between 473 and 811 μmol per liter (8.0 to 13.7 mg per deciliter) at some time during the 24-week period.
Dose Modifications
Therapy was discontinued in the two patients who had pancreatitis. In one, ddI was begun again 6 weeks later at one third the original dose (180 mg per square meter per day), and 22 weeks later this dose was increased to 270 mg per square meter per day. The patient has continued on this dose without sequelae for another 29 weeks.
Because pancreatitis and peripheral neuropathy had been found to be dose-limiting toxic effects in adult recipients of ddI, dose escalations were limited in this study once the levels associated with the potential for toxicity were reached. Thus, a maximal tolerated dose was not defined in this study. We found, however, that doses of up to 540 mg of ddI per square meter per day could safely be administered to children with little acute or subacute toxicity.
Clinical and Laboratory Responses to ddI
Table 4Table 4
Changes in Clinical, Immunologic, and Virologic Indexes in Response to Treatment with ddI. summarizes the clinical responses we observed. Weight gain and a reduction in the degree of lymphadenopathy and organomegaly were observed at all dose levels and in both previously treated and untreated patients (Table 5Table 5
Changes in Clinical, Immunologic, and Virologic Indexes in Response to Treatment with ddI in Previously Treated and Untreated Patients.*); a clear dose-related effect was not evident, however. All three patients who were enrolled with thrombocytopenia refractory to intravenous immune globulin as a major manifestation of HIV infection responded to ddI and have had platelet counts between 35 and 497×109 per liter for 36 to 50 weeks without additional intravenous immunoglobulin.Analysis of paired CD4 counts obtained at base line and after 20 to 24 weeks of treatment with ddI was possible for 38 patients; it revealed a significant increase in the median CD4 count after therapy (from 0.218 to 0.327×109 per liter, P = 0.001). Of the 43 patients enrolled, 13 (30 percent) had an increase in the CD4 count by week 24 of therapy; an additional patient had responded by week 12 but did not complete the 24-week course. Figure 1Figure 1
Effect of ddI on Surrogate Markers of HIV Infection.A shows the median CD4 counts over time for patients who completed the 24 weeks of ddI treatment as well as for those who did not. Of the eight patients who did not complete 24 weeks of ddI, six died, one was withdrawn because of progressive disease, and the other because of toxicity. All eight patients had advanced disease; six had a CD4 count below 0.05×109 per liter (<50 per cubic millimeter) at entry. Improvements were observed at all dose levels (Table 4) and in previously untreated patients as well as those with refractory disease or intolerance to zidovudine (Table 5). The factor that best predicted an increase in the CD4 count in response to ddI was the absolute CD4 count at the time of enrollment. An increase in the CD4 count that met the criteria for a response occurred in 11 of 22 patients who had a CD4 count above 0.1×109 per liter (100 per cubic millimeter) at entry, as compared with only 2 of 21 patients who had CD4 counts below 0.1×109 per liter (100 per cubic millimeter) at entry (P = 0.001 by Fisher's exact test). The CD4:CD8 ratio increased in 13 patients (30 percent), 8 of whom had had an increase in the CD4 cell count that met the criteria for a response. Although the remaining five patients had increases in the CD4 count above their base-line values, they did not meet our definition of a response. IgG levels were monitored in 40 patients and were elevated for age in 32 (80 percent). In 10 patients a reduction of more than 10 percent from the base-line value occurred during therapy.Serum p24 antigen was detectable in 32 patients (74 percent) at enrollment, and the level was above 100 pg per milliliter in 30 patients. Paired values for the p24 antigen level were available for 27 of the 32 patients with detectable antigen at entry; analysis revealed a significant decline in their median p24 antigen level, from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005 by the Wilcoxon signed-rank test). Furthermore, a dose-related effect was apparent (Fig. 1B), especially at 360 and 540 mg per square meter per day, the highest dose levels (P = 0.008 by the MantelHaenszel test) (Table 4). Moreover, patients who responded with declines in p24 antigen level had a higher median AUC than nonresponders (1.93 vs. 0.79 μmol · hour per liter, P = 0.002 by the Mann—Whitney test). In 19 of 32 patients (59 percent), p24 antigen levels decreased by at least 50 percent of the base-line value. When even more stringent criteria were used for improvement (counting only patients with levels above 100 pg per milliliter at entry who had a decrease to below 50 pg per milliliter at the final two evaluations), 12 of 30 patients (40 percent) had a response.
Twenty patients (47 percent) had abnormal chest radiographs at base line. Although only five patients had a history of lymphoid interstitial pneumonitis, infiltrates were described as diffuse, interstitial, or nodular in 16 patients. These remained largely unaffected by treatment with ddI; definite improvement was noted, however, in two patients, and radiographic evidence of the progression of disease was noted in three. CT scans of the head were obtained for 41 patients at base line; they were abnormal in 19 (46 percent). Cerebral atrophy and calcification of the basal ganglia and white matter were the most common abnormalities. Thirteen of these 19 patients had repeat scanning after 24 weeks of ddI therapy; the abnormalities were unchanged in 9 patients, improved in 2, and worse in 2. Of 22 patients with a normal CT scan of the head, 18 had a second evaluation at week 24; in 3 cases the appearance of mild cerebral atrophy was noted. Base-line brain images were obtained by MRI in 34 patients and were abnormal in 14 (41 percent). Eight children who had abnormal scans at entry had a repeat study after 24 weeks; an increase in the areas of signal intensity was noted in two patients, and improvement in involutional changes was observed in one patient. The MRI scan remained unchanged in 12 of 13 patients who had a normal scan at base line; in 1 patient mild cerebral atrophy was noted.
Neuropsychological Response
The results of neuropsychological assessments at base line and after 24 weeks were available for 34 of 35 children who completed 24 weeks of treatment with ddI. There was no change in the mean IQ score after 24 weeks. From a neurodevelopmental standpoint, however, this was an extremely disparate group of children. At entry, 11 of the 34 children (32 percent) had encephalopathy and had full-scale IQs below the normal range (mean, 64.6; range, 35 to 84), 14 patients had IQ scores in the normal range (90 to 110), and 9 children had IQs above 110. Individual response was therefore also assessed. After 24 weeks of ddI therapy there was an increase in the IQ score (>8 IQ points and 10 percent above base line) in 2 of the 11 patients with encephalopathy and in 4 of 14 patients with base-line IQ scores in the normal range. No change was detected in the nine children with IQs above 110 at base line. Changes in IQ scores after six months of ddI therapy were not influenced by previous antiretroviral treatment, method of acquisition of HIV, presence or absence of encephalopathy, or changes in the patient's CD4 count or p24 antigen level in response to ddI treatment (P>0.35). In the 34 patients for whom data were available there was no correlation between the dose of ddI and the degree of improvement in psychometric function. In the 26 patients for whom the results of both pharmacokinetic monitoring and neuropsychometric testing were available, however, a significant correlation was found between the plasma concentration of ddI after oral administration (AUC) and the change in IQ score (P = 0.05, r = 0.39). This correlation was strongest for the children whose IQ scores were in the normal range at base line (P<0.01, r = 0.64).
Discussion
In this study we found that ddI was well tolerated by children and that there was clear evidence of antiretroviral activity both in children who had received no previous antiretroviral therapy and in those treated with zidovudine in whom refractory disease or intolerance to zidovudine had developed. In the adult phase I studies to date,12 , 13 pancreatitis has been the most serious adverse reaction to ddI. In our study, pancreatitis developed in 2 of 43 children, 1 of whom was receiving 360 mg of ddI per square meter per day (10.7 mg per kilogram per day) and the other 540 mg per square meter per day (16.2 mg per kilogram per day). As in adults, the pancreatitis appeared to be related to the ddI treatment and resolved promptly when ddI was discontinued. The first patient had recently completed a course of intravenous pentamidine and was receiving aerosolized pentamidine and antituberculous therapy when pancreatitis developed. Pancreatitis has previously been attributed to both systemic and aerosolized pentamidine,17 , 18 and in the study by Lambert et al.,12 three of the five subjects in whom it developed were receiving this drug as prophylaxis. It is plausible that the concomitant administration of pentamidine may enhance individual susceptibility to ddI-induced pancreatitis. No cases of peripheral neuropathy were observed in our study.
The antiretroviral activity of ddI was evidenced by improvements over base-line values in clinical, laboratory, immunologic, and virologic indexes. Notable correlations of clinical response with the results of pharmacokinetic monitoring were also observed in this study. Although increases in CD4 counts have been reported in adults treated with ddI, few patients received ddI for more than 20 weeks in these series.11 12 13 The data presented here on a cohort of patients who received ddI for at least 20 weeks convincingly show an increase in CD4 counts with ddI therapy. Furthermore, the response to ddI appears to be more sustained than with zidovudine. With zidovudine therapy, increments in CD4 counts usually peak after two to three months of therapy and values return to base-line levels four to six months after the initiation of treatment.2 , 4 , 5 , 19 In this study, in most patients in whom the CD4 count increased after 12 weeks of ddI therapy that response was maintained over at least a 24-week period. Indeed, in some the improvement has persisted for over a year.
Children who entered this study with a CD4 count above 0.1×109 per liter (100 per cubic millimeter) were significantly more likely to have an increase in the CD4 count than those entering with a CD4 count below 0.1×109 per liter. There appears to be a critical threshold below which the probability of responding to antiretroviral therapy with an increase in the CD4 count is very small. Moreover, the normal CD4 count in infants and children appears to be several times higher than the normal adult level.20 Thus, the degree of immune impairment measured by the CD4 count is more profound for the children we studied than for adults with similar CD4 levels. The virologic response to ddI was dramatic, with marked declines in p24 antigen levels. Whereas the increases in the CD4 count were not dose-dependent, the decline in the p24 antigen level was clearly dose-related.
Although the plasma concentration of ddI (indicated by the AUC) after intravenous and oral administration is dose-dependent, there was considerable variation among patients in the absorption of ddI after oral administration, even when ddI was given under optimal conditions (i.e., in a supervised setting). The importance of this variability is exemplified by the results of neuropsychometric testing presented here. Cognitive improvement, as measured by full-scale IQ testing, did not correlate with the dose of ddI itself, but it did correlate significantly with the AUC for the patient. Indeed, the variability among patients in the bioavailability of ddI may well account for the lack of a dose-related effect on some of the surrogate markers of disease activity in this and other studies.
The significance of the relation among the plasma concentration of ddI (AUC), the ddI dose, and both the degree of cognitive improvement and the change in the p24 antigen level observed in this study underscores the importance of considering the pharmacokinetics and bioavailability of antiretroviral agents when assessing their activity and emphasizes the need to study further the factors that might affect them. Attention must also be focused on developing convenient methods of monitoring plasma drug concentrations. Adjustment of the dose should reflect not only the development of toxicity or a clinical response but also consideration of the optimal plasma concentration.
These data confirm that ddI is an important part of the antiretroviral repertoire. Although pancreatitis developed in some patients, doses up to 540 mg of ddI per square meter per day were generally well tolerated and did not lead to serious hematologic toxicity. Thus, ddI may be of benefit both in the initial treatment of HIV infection and in the treatment of patients with toxic hematologic effects due to zidovudine. Optimal benefits from ddI may require individualized pharmacokinetic monitoring and dose adjustment, however. Studies to address these important issues should help to refine the use of ddI in the treatment of HIV disease in both children and adults.
Source Information
From the Pediatric Branch (K.M.B., R.N.H., F.M.B., P.B., J.E., J.G., M.H., D.P., S.S., L.W., P.A.P.) and the Biostatistics and Data Management Section (D.V.), Clinical Oncology Program, National Cancer Institute, and the Pharmacy Department, Clinical Center (P.J.), National Institutes of Health, Bethesda, Md., and Medical Illness Counseling, Bethesda, Md. (D.E.-A., H.M., P.W.). Address reprint requests to Dr. Pizzo at the Pediatric Branch, National Cancer Institute, National Institutes of Health, Bldg. 10, Rm. 13N240, Bethesda, MD 20892.
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