RESEARCH/PRACTICE REPORTS
DIDANOSINE THERAPY IN PATIENTS INTOLERANT OF OR FAILING ZIDOVUDINE THERAPY R. Chris Rathbun and Emory S. Martin III
OBJECTIVE: To examine the effect of didanosine (2',3'dideoxyinosine, ddI) on surrogate markers of HIV infection (CD4+ lymphocyte count, p24 antigen) and to evaluate the incidence of adverse effects from ddI.
This study was performed as a retrospective chart review of patients who were enrolled in Bristol-Myers Squibb's expandedaccess program for ddI.
DESIGN:
Patient records were obtained from primary care physicians' offices.
SETIlNG:
Twenty-five HIV-infected patients diagnosed with AIDS or AIDS-related complex (ARC) who were intolerant of zidovudine (ZDV) therapy or deteriorating clinically despite ZDV therapy and were eligible for inclusion in the ddI expanded-access program.
PATIENTS:
INTERVENTION: ddI was administered orally in a citrate-phosphate buffer every 12 hours. Patients were followed by their private physician on a monthly basis. MAIN OlffCOME MEASURF.s: Laboratory analysis at each month included CD4+ lymphocyte count, hemoglobin, hematocrit, serum amylase, uric acid, serum triglycerides, and p24 antigen. Mean CD4+ cell count, serum amylase, hemoglobin, and uric acid at each month during ddI therapy were compared with baseline concentrations for nine months.
Patients had received prior ZDV therapy for an average of 15.5 months before starting ddI. Mean CD4+ cell counts increased from 53.9/mm3 at baseline to 72.4/mm3 after 4 months of therapy (p=O.04) but returned to concentrations comparable with those at baseline after 5 months. One case of documented pancreatitis, two cases of suspected pancreatitis, and nine cases of peripheral neuropathy occurred during ddI therapy. The estimated mean cumulative dose for the development of neuropathy was 1.16 g/kg, which is lower than previously reported. RESULTS:
Patients who have received prolonged therapy with ZDV or who have low initial CD4+ counts may not have sustained increases in CD4+ counts from ddI therapy. Also, development of peripheral neuropathy may occur at lower cumulative doses in these patient populations.
CONCLUSIONS:
Ann Pharmacother 1992;26: 1347-51. R. CHRIS RATHRUN, Pharm.D.• BCPS. is an Assistant Professor, Section of Pharmacy Practice, College of Pharmacy. University of Oklahoma, P.O. Box 26901, Oklahoma City, OK 73190; and EMORY S. MARTIN III, Pharm.D., is a Clinical Assistant Professor, Clinical Division, College of Pharmacy, University of Texas at Austin, and a Clinical Pharmacy Coordinator, Seton Medical Center, Austin, TX. Reprints: R. Chris Rathbun, Pharm.D.
is a purine analog with in vitro antiretroviral activity! that has been approved for the treatment of AIDS in patients intolerant of or deteriorating despite therapy with zidovudine (ZDV). ZDV was previously the only approved antiretroviral agent for AIDS2; however, neutropenia and anemia seen with ZDV therapy may limit its usefulness in some patients. Additionally, there is evidence that strains of HIV may develop resistance to ZDV over time.' Didanosine, like ZOY, is activated by intracellular phosphorylation to its active dideoxyadenosine triphosphate (ddA-TP) form. Because ddA-TP has a long duration of intracellular effect (half-life 12 h)," ddI has been dosed on a twice-daily basis and may potentially be effective when given once daily." Unlike ZDV, ddI does not appear to cause bone marrow suppression' and is active against strains of HIV that are resistant to ZDV.3 Therefore, it provides an alternative for patients who cannot tolerate ZDV or who are deteriorating despite treatment with ZOY. The purpose of this study was to examine the incidence of adverse effects during ddI therapy and the drug's effect on CD4+ lymphocytes (helper T cells) in a population intolerant of or failing ZDV therapy. Additionally, the effect of ddI on other laboratory parameters and p24 antigen in patients who had antigenernia prior to starting ddI was also studied,
OlDANOSINE (2',3'-OlDEOXYINOSINE, DOl)
Methods We retrospectively evaluated the records of 25 patients treated by three private physicians who were enrolled into Bristol-Myers Squibb's ddI expanded-access program during October 26,1989, to August 10, 1990. Patients who were eligible to receive ddI showed evidence of intolerance to ~oo mg/d of ZDV (sustained decreases in hemoglobin [20 gIL/mo] or neutrophils [ 1000 unitsJL]) and either had AIDS or symptomatic HIV disease AIDS-related complex (ARC) with a CD4+ count 49 kg were given 167 mg bid, 50-74 kg were given 250 mg bid; and 2':75 kg were given 375 mg bid. Data collected on each patient included dose of ddI administered, adverse effects during ddI therapy, length of prior ZDV use, and status of HIV disease. Laboratory data were collected for the physician visit prior to starting ddI and for each monthly visit while the patient was receiving ddI and included CD4+ lymphocyte count; absolute lymphocyte count; white blood cell count; and serum amylase, hemoglobin, hematocrit, serum triglycerides, uric acid, and p24 antigen concentrations. Statistical analysis was performed by comparing mean CD4+ cell counts for the study population at each month with mean CD4+ counts at baseline using the Wilcoxon signed-rank test (two-tailed) for paired samples. A p value :'>0.05 was considered statistically significant. Additionally, changes in hemoglobin, uric acid, and serum amylase were also compared at baseline and at each month during the study period using a paired t-test (two-tailed); a p value :'>0.05 was defined as statistically significant.
line levels (range - 41 to + 197) compared with an average increase of 46.1/mm3 (range -9 to +289) in the 17 who had baseline counts 0.05). Despite the short-lived increases in CD4+ counts in most patients, 13 of 25 patients did report a subjective improvement in their energy level after starting ddL Measurement of p24 antigen was performed at a commerciallaboratory by nonquantitative enzyme immunoassay (Abbott Laboratories, Chicago). Fifteen patients had detectable p24 antigen concentrations at the time of study entry. Five patients cleared their antigenemia for a portion of the study period. One patient became free of detectable antigen after 2 months of therapy and has remained free of detectable antigen for 16 months. Another patient cleared his antigenemia after 3 months of ddI and remained clear for an additional 5 months. The remaining three patients cleared their initial antigenemia within 2 or 3 months after starting ddI but subsequently relapsed within 1 or 2 months. There was no significant change in the concentration of hemoglobin or uric acid while patients were receiving ddI. Although the mean serum amylase for the study population stayed within normal limits (25-125 units/L), the mean concentration increased significantly after three months of treatment and remained elevated throughout the evaluation period; these results are summarized in Table 2. There were a number of adverse events reported during ddI treatment; 13 patients (52 percent) had therapy discon-
Table 1. Mean CD4+ Count with Tune
Results A total of 25 patients (24 men, 1 woman) were included in the analysis. Sixteen patients had a diagnosis of AIDS and 9 had ARC. AIDS-defining illnesses included Pneumocystis carinii pneumonia (6), cryptococcal meningitis (3), wasting syndrome (2), Candida esophagitis (1), HIV encephalitis (I), disseminated histoplasmosis (1), cytomegalovirus retinitis (1), and Kaposi's sarcoma (1). Mean CD4+ cell count for the study population prior to initiation of ddI was 53.9/mm3 (range 2-247). Patients had received ZDV for an average of 15.5 months (range 2.0-32.6) prior to starting ddL Six patients were started on ddI 375 mg bid, 18 on 250 mg bid, and 1 on 167 mg bid. Three patients had their ddI dosage decreased from 375 to 250 mg bid and 1 from 250 to 167 mg bid because of adverse effects believed to be caused by ddI (increases in liver function tests, persistent headaches, diarrhea). Mean CD4+ counts for the study period are summarized in Table 1. Counts increased in 15 of 23 patients after two months and in 18 of 23 patients after three months; however, increases were seen as soon as two weeks in some patients. Only I patient consistently maintained counts above those at baseline throughout the nine-month evaluation period. There was a statistically significant increase in mean CD4+ counts from baseline levels at month 4 of treatment with ddI; however, this increase was transient with CD4+ cell counts returning to levels below those at baseline by month 5 (p=0.03). Mean CD4+ counts did increase dramatically in month 3 (range 4-418), but because of the large variability in the data, this increase was not statistically significant. Over the entire study period, the 8 patients with CD4+ counts >50 cells/rum' at baseline had an average maximum count increase of 70.0/mm3 from base1348 •
The Annals ofPharmacotherapy
•
MONTH
0 I 2 3 4 5 6 7 8 9
NO. OF PATIENTS"
MEAN CD4+ CELLS (cells/mrrr')
RANGE (cells/mar')
25/25 19/25 19/23 18/23 20/23 17/19 17117 11/13
53.9 51.0 53.7 103.3 72.4 47.4 65.2 65.9 46.3 54.8
2-247 3-182 0-294 4-418 3-305 2-192 7-352 11-238 5-217 6-202
7/7 5/5
pVALUE
NS NS 0.08 0.04 b 0.03 b NS NS NS NS
ddI = didanosine; NS = not significant. "Number of patients whose physician visit corresponds with the respective month versus total number of patients on ddI. bStatistically significant (Wilcoxon's signed-rank sum) compared with month O.
Table 2. Mean (± SD) Serum Amylase with Tune
MONTH
0 1 2 3 4 5 6 7 8 9
NO. OF PATIENTS
23/25 19/25 21/23 20/23 20/23 16/19 17/17 12/13
7/7 5/5
MEAN SERUM AMYLASE" (units/l.)
RANGE (units/L)
68.8± 26.9 77.1 ± 32.2 73.4± 26.6 88.0±43.2 95.6 ± 60.2 86.8 ± 30.2 93.1 ± 39.6 93.2 ± 31.2 89.0 ± 31.9 77.4 ± 31.6
24-129 37-164 19-148 28-249 23-313 29-150 29-209 38-139 33-133 33-121
pVALUE
NS NS
o.oi-
0.03 b 0.07 0.02 b 0.02 b NS NS
NS = not significant. "Normal range = 25-125 units/L. bStatistically significant (paired t-test, p:'>0.05) compared with month O.
1992 November, Volume 26
Research/Practice
tinued. Nine patients developed symptoms of neuropathy during ddI therapy or shortly after discontinuation. Therapy was discontinued in 6 patients after symptoms developed. Three other patients were discontinued from ddI for other reasons (increased amylase, suspected pancreatitis), but developed symptoms of neuropathy prior to discontinuation, within two days of discontinuation, and five weeks after therapy was stopped. Symptoms of neuropathy were described as tingling or numbness in the soles of the feet or fingers or as sharp pains or tenderness in the feet. Only 2 patients reported symptoms involving the hands with I having concomitant symptoms in the feet. Neuropathy commonly was not seen until after 5.5 months of therapy; however, symptoms occurred as early as after 1.5 months of treatment. We attempted to estimate the cumulative dose of ddI that these patients had received, taking into account any documented interruptions in therapy. Assuming that patients were I()() percent compliant, we calculated a cumulative dose for each patient based on their weight at baseline and their daily dose of ddI; results are summarized in Table 3. The average cumulative dose from these results was determined to be 1.16 g/kg. Three patients had neuropathy prior to beginning ddI. Therapy was discontinued in I patient when his symptoms worsened and is included in those described above; however, 2 patients were able to tolerate ddI despite their baseline neuropathy and did not exhibit a deterioration in their condition. Three patients had therapy discontinued for suspected pancreatitis secondary to ddI. Two of them were hospitalized because of the acute and severe nature of their symptoms, with one patient having documented computed tomography fmdings consistent with pancreatitis. Two of the three patients were receiving nebulized pentamidine concurrent with ddI therapy. An additional patient was discontinued from ddI therapy because of progressive increases in serum amylase but remained asymptomatic. Serum amylase concentrations for this group of patients are summarized in Figure 1. One patient developed hypertension which was believed to be secondary to the sodium content in the ddI formulation. Therapy was discontinued for one month, and the patient was started on a new formulation prepared by the manufacturer without subsequent difficulties. The most common adverse effect reported was diarrhea (52 percent), which ranged from mild to massive and often exacerbated preexistent diarrhea. The manufacturer reports
that this may have been related to the citrate-phosphate buffer that was present in the ddI formulation used in the expanded-access program and, therefore, could be reduced with the new formulation that is currently marketed. There were also six reports of rash developing during ddI therapy; however, all cases were attributed to concomitant therapy (amoxicillin, penicillin, dapsone, doxycycline, allopurinol, and ciprofloxacin). Other adverse effects responsible for discontinuation of ddI were agitation in one patient, persistent abdominal pain and diarrhea in another, and neutropenia in one patient who was later found to have Mycobacterium avium-intracellulare in his bone marrow.
Discussion Previous reports of experience with ddI have shown variable CD4+ cell count responses in patients who have received prior ZDV therapy. Some investigators have observed no apparent effect from previous ZDVs; others have stated that increases in CD4+ cell counts are less dramatic or even absent in patients who have received ZDV.7,8 Our observations suggest that the response to ddI may be less impressive in patients who have received ZDV, particularly in those who have been taking ZDV for an extended period of time. This is reflected in the minimal increase in CD4+ counts in the majority of patients in our study and their average length of therapy with ZDV (I5.5 months) prior to starting ddI. Despite a lack of a sustained increase in the number of CD4+ cells, these severely immunocompromised patients did, on average, maintain a consistent CD4+ cell count throughout the evaluation period and did
600
~ .l!l 'c
2C1l
Ul
400
Cll
>,
E
50/mm3 at baseline (70.0/mm3) with those with CD4+ counts
DIDANOSINE THERAPY IN PATIENTS INTOLERANT OF OR FAILING ZIDOVUDINE THERAPY R. Chris Rathbun and Emory S. Martin III
OBJECTIVE: To examine the effect of didanosine (2',3'dideoxyinosine, ddI) on surrogate markers of HIV infection (CD4+ lymphocyte count, p24 antigen) and to evaluate the incidence of adverse effects from ddI.
This study was performed as a retrospective chart review of patients who were enrolled in Bristol-Myers Squibb's expandedaccess program for ddI.
DESIGN:
Patient records were obtained from primary care physicians' offices.
SETIlNG:
Twenty-five HIV-infected patients diagnosed with AIDS or AIDS-related complex (ARC) who were intolerant of zidovudine (ZDV) therapy or deteriorating clinically despite ZDV therapy and were eligible for inclusion in the ddI expanded-access program.
PATIENTS:
INTERVENTION: ddI was administered orally in a citrate-phosphate buffer every 12 hours. Patients were followed by their private physician on a monthly basis. MAIN OlffCOME MEASURF.s: Laboratory analysis at each month included CD4+ lymphocyte count, hemoglobin, hematocrit, serum amylase, uric acid, serum triglycerides, and p24 antigen. Mean CD4+ cell count, serum amylase, hemoglobin, and uric acid at each month during ddI therapy were compared with baseline concentrations for nine months.
Patients had received prior ZDV therapy for an average of 15.5 months before starting ddI. Mean CD4+ cell counts increased from 53.9/mm3 at baseline to 72.4/mm3 after 4 months of therapy (p=O.04) but returned to concentrations comparable with those at baseline after 5 months. One case of documented pancreatitis, two cases of suspected pancreatitis, and nine cases of peripheral neuropathy occurred during ddI therapy. The estimated mean cumulative dose for the development of neuropathy was 1.16 g/kg, which is lower than previously reported. RESULTS:
Patients who have received prolonged therapy with ZDV or who have low initial CD4+ counts may not have sustained increases in CD4+ counts from ddI therapy. Also, development of peripheral neuropathy may occur at lower cumulative doses in these patient populations.
CONCLUSIONS:
Ann Pharmacother 1992;26: 1347-51. R. CHRIS RATHRUN, Pharm.D.• BCPS. is an Assistant Professor, Section of Pharmacy Practice, College of Pharmacy. University of Oklahoma, P.O. Box 26901, Oklahoma City, OK 73190; and EMORY S. MARTIN III, Pharm.D., is a Clinical Assistant Professor, Clinical Division, College of Pharmacy, University of Texas at Austin, and a Clinical Pharmacy Coordinator, Seton Medical Center, Austin, TX. Reprints: R. Chris Rathbun, Pharm.D.
is a purine analog with in vitro antiretroviral activity! that has been approved for the treatment of AIDS in patients intolerant of or deteriorating despite therapy with zidovudine (ZDV). ZDV was previously the only approved antiretroviral agent for AIDS2; however, neutropenia and anemia seen with ZDV therapy may limit its usefulness in some patients. Additionally, there is evidence that strains of HIV may develop resistance to ZDV over time.' Didanosine, like ZOY, is activated by intracellular phosphorylation to its active dideoxyadenosine triphosphate (ddA-TP) form. Because ddA-TP has a long duration of intracellular effect (half-life 12 h)," ddI has been dosed on a twice-daily basis and may potentially be effective when given once daily." Unlike ZDV, ddI does not appear to cause bone marrow suppression' and is active against strains of HIV that are resistant to ZDV.3 Therefore, it provides an alternative for patients who cannot tolerate ZDV or who are deteriorating despite treatment with ZOY. The purpose of this study was to examine the incidence of adverse effects during ddI therapy and the drug's effect on CD4+ lymphocytes (helper T cells) in a population intolerant of or failing ZDV therapy. Additionally, the effect of ddI on other laboratory parameters and p24 antigen in patients who had antigenernia prior to starting ddI was also studied,
OlDANOSINE (2',3'-OlDEOXYINOSINE, DOl)
Methods We retrospectively evaluated the records of 25 patients treated by three private physicians who were enrolled into Bristol-Myers Squibb's ddI expanded-access program during October 26,1989, to August 10, 1990. Patients who were eligible to receive ddI showed evidence of intolerance to ~oo mg/d of ZDV (sustained decreases in hemoglobin [20 gIL/mo] or neutrophils [ 1000 unitsJL]) and either had AIDS or symptomatic HIV disease AIDS-related complex (ARC) with a CD4+ count 49 kg were given 167 mg bid, 50-74 kg were given 250 mg bid; and 2':75 kg were given 375 mg bid. Data collected on each patient included dose of ddI administered, adverse effects during ddI therapy, length of prior ZDV use, and status of HIV disease. Laboratory data were collected for the physician visit prior to starting ddI and for each monthly visit while the patient was receiving ddI and included CD4+ lymphocyte count; absolute lymphocyte count; white blood cell count; and serum amylase, hemoglobin, hematocrit, serum triglycerides, uric acid, and p24 antigen concentrations. Statistical analysis was performed by comparing mean CD4+ cell counts for the study population at each month with mean CD4+ counts at baseline using the Wilcoxon signed-rank test (two-tailed) for paired samples. A p value :'>0.05 was considered statistically significant. Additionally, changes in hemoglobin, uric acid, and serum amylase were also compared at baseline and at each month during the study period using a paired t-test (two-tailed); a p value :'>0.05 was defined as statistically significant.
line levels (range - 41 to + 197) compared with an average increase of 46.1/mm3 (range -9 to +289) in the 17 who had baseline counts 0.05). Despite the short-lived increases in CD4+ counts in most patients, 13 of 25 patients did report a subjective improvement in their energy level after starting ddL Measurement of p24 antigen was performed at a commerciallaboratory by nonquantitative enzyme immunoassay (Abbott Laboratories, Chicago). Fifteen patients had detectable p24 antigen concentrations at the time of study entry. Five patients cleared their antigenemia for a portion of the study period. One patient became free of detectable antigen after 2 months of therapy and has remained free of detectable antigen for 16 months. Another patient cleared his antigenemia after 3 months of ddI and remained clear for an additional 5 months. The remaining three patients cleared their initial antigenemia within 2 or 3 months after starting ddI but subsequently relapsed within 1 or 2 months. There was no significant change in the concentration of hemoglobin or uric acid while patients were receiving ddI. Although the mean serum amylase for the study population stayed within normal limits (25-125 units/L), the mean concentration increased significantly after three months of treatment and remained elevated throughout the evaluation period; these results are summarized in Table 2. There were a number of adverse events reported during ddI treatment; 13 patients (52 percent) had therapy discon-
Table 1. Mean CD4+ Count with Tune
Results A total of 25 patients (24 men, 1 woman) were included in the analysis. Sixteen patients had a diagnosis of AIDS and 9 had ARC. AIDS-defining illnesses included Pneumocystis carinii pneumonia (6), cryptococcal meningitis (3), wasting syndrome (2), Candida esophagitis (1), HIV encephalitis (I), disseminated histoplasmosis (1), cytomegalovirus retinitis (1), and Kaposi's sarcoma (1). Mean CD4+ cell count for the study population prior to initiation of ddI was 53.9/mm3 (range 2-247). Patients had received ZDV for an average of 15.5 months (range 2.0-32.6) prior to starting ddL Six patients were started on ddI 375 mg bid, 18 on 250 mg bid, and 1 on 167 mg bid. Three patients had their ddI dosage decreased from 375 to 250 mg bid and 1 from 250 to 167 mg bid because of adverse effects believed to be caused by ddI (increases in liver function tests, persistent headaches, diarrhea). Mean CD4+ counts for the study period are summarized in Table 1. Counts increased in 15 of 23 patients after two months and in 18 of 23 patients after three months; however, increases were seen as soon as two weeks in some patients. Only I patient consistently maintained counts above those at baseline throughout the nine-month evaluation period. There was a statistically significant increase in mean CD4+ counts from baseline levels at month 4 of treatment with ddI; however, this increase was transient with CD4+ cell counts returning to levels below those at baseline by month 5 (p=0.03). Mean CD4+ counts did increase dramatically in month 3 (range 4-418), but because of the large variability in the data, this increase was not statistically significant. Over the entire study period, the 8 patients with CD4+ counts >50 cells/rum' at baseline had an average maximum count increase of 70.0/mm3 from base1348 •
The Annals ofPharmacotherapy
•
MONTH
0 I 2 3 4 5 6 7 8 9
NO. OF PATIENTS"
MEAN CD4+ CELLS (cells/mrrr')
RANGE (cells/mar')
25/25 19/25 19/23 18/23 20/23 17/19 17117 11/13
53.9 51.0 53.7 103.3 72.4 47.4 65.2 65.9 46.3 54.8
2-247 3-182 0-294 4-418 3-305 2-192 7-352 11-238 5-217 6-202
7/7 5/5
pVALUE
NS NS 0.08 0.04 b 0.03 b NS NS NS NS
ddI = didanosine; NS = not significant. "Number of patients whose physician visit corresponds with the respective month versus total number of patients on ddI. bStatistically significant (Wilcoxon's signed-rank sum) compared with month O.
Table 2. Mean (± SD) Serum Amylase with Tune
MONTH
0 1 2 3 4 5 6 7 8 9
NO. OF PATIENTS
23/25 19/25 21/23 20/23 20/23 16/19 17/17 12/13
7/7 5/5
MEAN SERUM AMYLASE" (units/l.)
RANGE (units/L)
68.8± 26.9 77.1 ± 32.2 73.4± 26.6 88.0±43.2 95.6 ± 60.2 86.8 ± 30.2 93.1 ± 39.6 93.2 ± 31.2 89.0 ± 31.9 77.4 ± 31.6
24-129 37-164 19-148 28-249 23-313 29-150 29-209 38-139 33-133 33-121
pVALUE
NS NS
o.oi-
0.03 b 0.07 0.02 b 0.02 b NS NS
NS = not significant. "Normal range = 25-125 units/L. bStatistically significant (paired t-test, p:'>0.05) compared with month O.
1992 November, Volume 26
Research/Practice
tinued. Nine patients developed symptoms of neuropathy during ddI therapy or shortly after discontinuation. Therapy was discontinued in 6 patients after symptoms developed. Three other patients were discontinued from ddI for other reasons (increased amylase, suspected pancreatitis), but developed symptoms of neuropathy prior to discontinuation, within two days of discontinuation, and five weeks after therapy was stopped. Symptoms of neuropathy were described as tingling or numbness in the soles of the feet or fingers or as sharp pains or tenderness in the feet. Only 2 patients reported symptoms involving the hands with I having concomitant symptoms in the feet. Neuropathy commonly was not seen until after 5.5 months of therapy; however, symptoms occurred as early as after 1.5 months of treatment. We attempted to estimate the cumulative dose of ddI that these patients had received, taking into account any documented interruptions in therapy. Assuming that patients were I()() percent compliant, we calculated a cumulative dose for each patient based on their weight at baseline and their daily dose of ddI; results are summarized in Table 3. The average cumulative dose from these results was determined to be 1.16 g/kg. Three patients had neuropathy prior to beginning ddI. Therapy was discontinued in I patient when his symptoms worsened and is included in those described above; however, 2 patients were able to tolerate ddI despite their baseline neuropathy and did not exhibit a deterioration in their condition. Three patients had therapy discontinued for suspected pancreatitis secondary to ddI. Two of them were hospitalized because of the acute and severe nature of their symptoms, with one patient having documented computed tomography fmdings consistent with pancreatitis. Two of the three patients were receiving nebulized pentamidine concurrent with ddI therapy. An additional patient was discontinued from ddI therapy because of progressive increases in serum amylase but remained asymptomatic. Serum amylase concentrations for this group of patients are summarized in Figure 1. One patient developed hypertension which was believed to be secondary to the sodium content in the ddI formulation. Therapy was discontinued for one month, and the patient was started on a new formulation prepared by the manufacturer without subsequent difficulties. The most common adverse effect reported was diarrhea (52 percent), which ranged from mild to massive and often exacerbated preexistent diarrhea. The manufacturer reports
that this may have been related to the citrate-phosphate buffer that was present in the ddI formulation used in the expanded-access program and, therefore, could be reduced with the new formulation that is currently marketed. There were also six reports of rash developing during ddI therapy; however, all cases were attributed to concomitant therapy (amoxicillin, penicillin, dapsone, doxycycline, allopurinol, and ciprofloxacin). Other adverse effects responsible for discontinuation of ddI were agitation in one patient, persistent abdominal pain and diarrhea in another, and neutropenia in one patient who was later found to have Mycobacterium avium-intracellulare in his bone marrow.
Discussion Previous reports of experience with ddI have shown variable CD4+ cell count responses in patients who have received prior ZDV therapy. Some investigators have observed no apparent effect from previous ZDVs; others have stated that increases in CD4+ cell counts are less dramatic or even absent in patients who have received ZDV.7,8 Our observations suggest that the response to ddI may be less impressive in patients who have received ZDV, particularly in those who have been taking ZDV for an extended period of time. This is reflected in the minimal increase in CD4+ counts in the majority of patients in our study and their average length of therapy with ZDV (I5.5 months) prior to starting ddI. Despite a lack of a sustained increase in the number of CD4+ cells, these severely immunocompromised patients did, on average, maintain a consistent CD4+ cell count throughout the evaluation period and did
600
~ .l!l 'c
2C1l
Ul
400
Cll
>,
E
50/mm3 at baseline (70.0/mm3) with those with CD4+ counts
