Controlled Trial of Interleukin-2 Infusions in Patients Infected with the Human Immunodeficiency Virus
Joseph A. Kovacs, M.D., Susan Vogel, B.S., Jeffrey M. Albert, Ph.D., Judith Falloon, M.D., Richard T. Davey, M.D., Robert E. Walker, M.D., Michael A. Polis, M.D., M.P.H., Katherine Spooner, M.D., Julia A. Metcalf, B.A., Michael Baseler, Ph.D., Gwendolyn Fyfe, M.D., H. Clifford Lane, M.D., Robin J. Dewar, and Henry Masur
Background Interleukin-2 is a cytokine that regulates the proliferationand differentiation of lymphocytes. In preliminary studies,intermittent infusions of interleukin-2 led to increases inCD4 counts in patients with human immunodeficiency virus (HIV)infection and more than 200 CD4 cells per cubic millimeter.We conducted a controlled study to evaluate the long-term effectsof such therapy on both CD4 counts and the viral burden.
Methods Sixty HIV-infected patients with base-line CD4 countsabove 200 cells per cubic millimeter were randomly assignedto receive either interleukin-2 plus antiretroviral therapy(31 patients, 1 of whom was lost to follow-up) or antiretroviraltherapy alone (29 patients). Interleukin-2 was administeredevery two months for six cycles of five days each, startingat a dosage of 18 million IU per day. Safety and immunologicand virologic measures were monitored monthly until four monthsafter the last treatment cycle.
Results In patients treated with interleukin-2, the mean (±SE)CD4 count increased from 428±25 cells per cubic millimeterat base line to 916±128 at month 12, whereas in the controlgroup, the mean CD4 count decreased from 406±29 cellsper cubic millimeter to 349±41 (P<0.001). There wereno significant differences between the groups in serial measurementsof the plasma HIV RNA or p24 antigen concentration during the12 months of treatment. Constitutional symptoms (fever, malaise,and fatigue) and asymptomatic hyperbilirubinemia were the chiefdose-limiting toxic effects of interleukin-2 therapy.
Conclusions In patients with HIV infection and base-line CD4counts above 200 cells per cubic millimeter, intermittent infusionsof interleukin-2 produced substantial and sustained increasesin CD4 counts with no associated increase in plasma HIV RNAlevels.
The symptoms of infection with the human immunodeficiency virus(HIV) result from a progressive immunodeficiency due to thedestruction of CD4 T lymphocytes, which ultimately renders HIV-infectedpatients susceptible to opportunistic infections and malignantdisorders. Immune-system–based approaches to the treatmentof HIV infection use pharmacologic augmentation of immunityin an attempt to prevent, delay, or reverse this deterioration.1,2,3This approach is likely to be increasingly useful as the suppressionof viral replication by combinations of new, potent antiviralagents facilitates expansion of the immune system.4,5,6,7
Interleukin-2 is a cytokine secreted by activated T lymphocytesthat regulates the proliferation and differentiation of lymphocytes,including CD4 T cells.8,9,10,11 Although measurement of theviral burden indicates how fast the immune system will decline,the number or percentage of CD4 cells remains the best singleindicator of the capacity of the immune system to prevent thedevelopment of opportunistic infections.12,13,14,15,16 In anuncontrolled pilot study, intermittent interleukin-2 therapyresulted in sustained increases in the number of CD4 cells,primarily in patients with base-line CD4 counts greater than200 cells per cubic millimeter.17 The immune-system activationinduced by interleukin-2 therapy was associated with transientincreases in the plasma HIV load in some patients. To validatethese preliminary observations, and to determine the long-termeffects of intermittent interleukin-2 therapy on the HIV load,we carried out a randomized, controlled trial of intermittentinterleukin-2 therapy in HIV-infected patients with CD4 countsgreater than 200 cells per cubic millimeter.
Methods
Study Design
Patients 18 years or older who had HIV type 1 infection andCD4 counts above 200 cells per cubic millimeter at screeningwere eligible for enrollment if they had never received interleukin-2,had no history of an opportunistic infection defined as oneindicating progression to the acquired immunodeficiency syndrome(AIDS), and had received no corticosteroids, cytotoxic chemotherapy,or experimental therapy in the preceding four weeks. The studywas approved by the institutional review board of the NationalInstitute of Allergy and Infectious Diseases (NIAID), and allpatients provided written informed consent. The study was reviewedtwice by a five-member data and safety monitoring board.
Patients were randomly assigned to receive antiretroviral therapyplus intermittent intravenous infusions of interleukin-2 orantiretroviral therapy alone. For purposes of randomization,patients were stratified according to the CD4 count (>500or <500 cells per cubic millimeter) and plasma HIV RNA concentration(<10,000 or >10,000 HIV RNA copies per milliliter) measuredat screening. The study was not placebo controlled, so as toavoid unnecessary hospitalizations for the intravenous infusionof placebo, given that the constitutional side effects of interleukin-2make blinding impossible.
Patients were evaluated monthly for 14 months after randomization.Patients treated with interleukin-2 were hospitalized at theWarren Grant Magnuson Clinical Center every other month, frommonth 0 through month 10, for the administration of six cyclesof interleukin-2. Interleukin-2 (aldesleukin; Proleukin, Chiron,Emeryville, Calif.) was diluted in 5 percent aqueous dextrosesolution containing 0.1 percent albumin and administered bycontinuous infusion, starting at a dose of 18 million IU perday for five days, with dose reductions of 3 to 6 million IUas needed when there was clinical or laboratory evidence oftoxicity.17 Safety and immunologic and virologic measures wereassessed monthly for all patients; in the interleukin-2 group,laboratory values were obtained before each cycle of interleukin-2was begun. At the end of 14 months, all patients were eligibleto receive interleukin-2.
Antiretroviral therapy (with zidovudine, didanosine, zalcitabine,or stavudine, alone or in combination) was provided to all patients,and the agents used could be changed at any time during thecourse of the study. The specific regimen was determined bythe patient and the referring physician, in consultation withthe study team.
Measurement of lymphocyte subgroups and identification of surfacemarkers were performed according to the guidelines of the Centersfor Disease Control and Prevention.18 Particle-associated plasmaHIV RNA concentrations were determined with use of the branched-chainDNA assay (Chiron).19,20 Levels of p24 antigen were determinedby an immune-complex–dissociated assay (Coulter, Hialeah,Fla.).21
Statistical Analysis
The primary end point of the study was the effect of intermittentinterleukin-2 therapy on the CD4 count over time. Secondaryend points included changes in the plasma HIV load, level ofp24 antigenemia, percentage of CD4 cells, and number and percentageof CD8 cells. A sample of 60 patients was considered adequateto provide 90 percent power to detect a difference of 35 cellsper cubic millimeter in the CD4 count after one year, with atype I error of 0.05, assuming a 20 percent dropout rate. Changesover time for each individual patient were summarized for eachvariable by the difference between average base-line and post-treatmentmeasurements and by the ordinary least-squares estimate of theslope of the measurements over time. Base-line values (month0) were the means of the measurements made at two screeningvisits and the first study visit. Data were analyzed with useof the SAS System for Microsoft Windows, release 6.10 (SAS Institute,Cary, N.C.), according to the group to which the patient wasoriginally randomly assigned (intention-to-treat analysis).Two-sample t-tests (for unequal variances) were used to testfor differences between the group means; the results were confirmedwith the Wilcoxon rank-sum test. All statistical tests weretwo-sided, and a P value <0.05 was considered to indicatestatistical significance.22
To ensure that group differences were not attributable to observedimbalances at base line, we also tested the effect of treatmentwhile controlling for base-line covariates (CD4 count, viralload, and history of antiviral therapy) by means of multiplelinear regression.
Results
Sixty patients were enrolled in the study between April andDecember 1993. Thirty-one were randomly assigned to the interleukin-2group, and 29 to the control group. The base-line characteristicsof the two groups were similar when assessed by the chi-squareor Wilcoxon rank-sum test (Table 1). One patient assigned tointerleukin-2 withdrew from the study before receiving interleukin-2and was lost to follow-up. One patient in the control groupreceived interleukin-2 from his primary care physician duringthe initial 14 months of the study.
Table 1. Base-Line Characteristics According to Study Group.
There were no significant differences between the groups inantiviral regimens either at enrollment or during the study.Two thirds of the patients received combination antiretroviraltherapy. Sixty percent of the patients in the interleukin-2group had at least one change in their antiviral regimen duringthe study, as compared with 69 percent of the control group.
The 30 patients in the interleukin-2 group received 157 cyclesof interleukin-2. Ten patients missed a total of 23 cycles forthe following reasons: withdrawal from the study because ofintolerable side effects (five patients, 16 cycles); noncompliance(one patient, 2 cycles); a CD4 count above 3000 cells per cubicmillimeter (two patients, 3 cycles); anemia (one patient, 1cycle); and cardiomyopathy (one patient, 1 cycle). The meantotal dose per cycle decreased from 76 million IU for cycle1 to 39 million IU for cycle 6. At the same time, the percentageof patients completing a cycle without modification of the doseor premature discontinuation of the drug increased from 47 percentfor cycle 1 to 80 percent for cycle 6.
Moderate and severe clinical side effects and laboratory abnormalitiesthat occurred during the administration of interleukin-2 aresummarized in Table 2. Fatigue, malaise, and other constitutionalsymptoms were the most common clinical toxic effects (recordedfor 44 percent of cycles). Asymptomatic elevations of the bilirubinlevel were the most common laboratory abnormalities (8.3 percentof cycles). All patients had at least one moderate or severetoxic effect, primarily constitutional symptoms (which occurredin 90 percent of patients). Toxic effects decreased in frequencyas the dosage was decreased during later cycles.
Table 2. Moderate and Severe Clinical Side Effects and Laboratory Abnormalities in 30 Patients during 157 Cycles of Interleukin-2 Treatment.
No differences in routine indicators of the safety of therapywere identified by linear regression, or slope, analysis, exceptfor the total white-cell count, polymorphonuclear-cell count,and lymphocyte count, which showed a significant increase duringthe controlled study in the interleukin-2 group as comparedwith the control group (Table 3). When we examined the changein weight over time with linear regression, we found no significantdifference between the two groups; the interleukin-2 group hada mean (±SE) loss of 0.01±0.06 kg per month; thecontrol group, a loss of 0.17±0.06 kg per month (P =0.06).
Table 3. Changes in Immunologic and Virologic Measures According to Study Group.
In the interleukin-2 group hypothyroidism requiring thyroidsupplementation developed in two patients; psoriatic arthritisdeveloped in one patient with a history of psoriasis, but hecompleted the study at a reduced dose; one asymptomatic patientwas noted to have a cardiomyopathy of undetermined cause thatpersisted for over one year despite his receiving no furtherinterleukin-2; and one patient was given a diagnosis of Bowen'sdisease (squamous-cell carcinoma in situ).
Among the 29 patients in the control group, 10 had 32 episodesof moderate or severe clinical side effects or laboratory abnormalitiesduring the study period, including headache (18 episodes), fatigue(4 episodes), weight loss (1 episode), diarrhea (4 episodes),nausea or vomiting (1 episode), fever (1 episode), elevatedlipase concentration (>562 U per liter, 2 episodes), andelevation in the alanine aminotransferase concentration (>300U per liter, 1 episode).
During the 14 months of the study, one patient in the interleukin-2group died. This patient entered the study with a decliningCD4 count (mean base-line CD4 count, 188 cells per cubic millimeter)and received two shortened cycles of interleukin-2; he withdrewfrom the study because of intolerable side effects with a CD4count of 102 cells per cubic millimeter. He had a rapidly decliningCD4 count and a rising viral load; Mycobacterium avium bacteremiasubsequently developed (CD4 count, 51 cells per cubic millimeter[9 percent]), and he was given a presumptive diagnosis of progressivemultifocal leukoencephalopathy before his death, six monthsafter his entry into the study. No other patient in the interleukin-2group had an opportunistic infection during the 14-month controlledstudy.
Disseminated bacillary angiomatosis developed in one controlpatient at month 8 (CD4 count, 216 cells per cubic millimeter[10 percent]) but responded to therapy. A second patient inthe control group had focal central nervous system lesions atmonth 14 (CD4 count, 74 cells per cubic millimeter [9 percent])that responded to empirical anti-toxoplasma therapy.
Changes in Immunologic Measures
There was a significant difference in the mean slopes of theCD4 count over time between the two groups. In the interleukin-2group, the mean slope was +36.7 cells per month, whereas inthe control group it was -4.8 cells per month (P<0.001).Similarly, the percentage of CD4 cells also increased significantlyin the interleukin-2 group (Table 3). Both groups had a slightdrop in the CD8 cell count (P = 0.65); however, the percentageof CD8 cells increased slightly in the control group while decreasingin the interleukin-2 group (Table 3) (P<0.001).
Consistent with the slope analysis was the fact that both theCD4 cell count and the percentage of CD4 cells increased inthe interleukin-2 group during the period when interleukin-2was administered (Figure 1A and Figure 1B). Fifty-seven percentof the patients treated with interleukin-2 had an increase ofmore than 50 percent over the base-line CD4 count at the endof approximately one year (mean of the measurements in months11 and 12), as compared with none of the control group. Themean (±SE) net change from base line in the CD4 countat the end of the study (mean of the measurements at months13 and 14) was an increase of 412±96 cells per cubicmillimeter for the 29 surviving patients in the interleukin-2group and a decrease of 48±23 cells per cubic millimeterfor the 29 patients in the control group (P<0.001).
Figure 1. Mean and Median CD4 and CD8 Counts (Panel A) and Percentages (Panel B) and Mean Plasma Viral Load and p24 Antigen Level (Panel C) in the Interleukin-2 and Control Groups during the 14 Months of the Controlled Study.
The error bars represent ±2 SE and approximate the 95 percent confidence intervals. Values at month 0 (base line) are the means of three values measured before the beginning of the study. The shaded bars represent the times during which interleukin-2 was administered (month 0 to month 10). One patient received his sixth cycle of interleukin-2 at month 11. The numbers at the bottom of the panels indicate the numbers of patients for whom data were available.
Among the other immunologic measures that were monitored, theinterleukin-2 group had a significant decline in the percentageof CD8 cells that were positive for HLA-DR and a significantincrease in the number and percentage of CD4 cells that werepositive for CD25 (Table 3).
Changes in Virologic Measures
No significant differences were seen between the groups in themean slope over time for either HIV RNA levels (log-transformed)or p24 antigen levels (also log-transformed) (Figure 1C andTable 3). Similarly, no significant differences were seen betweenthe groups in the net change in these values from base lineto the end of the study (the mean of the values measured atmonths 13 and 14).
Correlates of the Response to Interleukin-2
There was a significant correlation between the CD4 responseto interleukin-2 therapy and the base-line CD4 count (P = 0.02),but not the base-line viral load. In the control group, therewas a significant inverse correlation between the base-lineviral load and the slope of the CD4 counts over time (P = 0.001).
Long-Term Follow-Up
After month 14, all patients were eligible to receive intermittentinterleukin-2 on an ongoing basis. Twenty-one patients in theinterleukin-2 group (19 of whom have continued in the study)and 24 in the control group (12 of whom are still in the study)elected to receive interleukin-2 during this extended studyperiod. Eleven patients, three in the interleukin-2 group andeight in the control group, subsequently enrolled in a studyexamining the combination of the protease inhibitor indinavirand intermittent interleukin-2.
Four patients died of AIDS-related complications during long-termfollow-up. Cryptosporidiosis developed at month 16 in one patientin the interleukin-2 group who had not had an increase in theCD4 count (CD4 count, 202 cells per cubic millimeter [9 percent]);he died six months later, approximately a year after his lastcycle of interleukin-2. Biopsy-documented progressive multifocalleukoencephalopathy developed in one control patient, at month18, during his third cycle of interleukin-2 (CD4 count, 144cells per cubic millimeter [9 percent]); he died two monthslater. Another control patient died with a wasting syndrome21 months after receiving two cycles of interleukin-2 (lastCD4 count, 18 cells per cubic millimeter [2 percent]). A thirdcontrol patient who never received interleukin-2 had Pneumocystiscarinii pneumonia 31 months after study enrollment (CD4 count,11 cells per cubic millimeter [2 percent]) and subsequentlydied. In addition, Hodgkin's disease (not an AIDS-defining disease)developed at month 16 in the patient in the interleukin-2 groupwho had had Bowen's disease (CD4 count, 792 cells per cubicmillimeter [18 percent]); P. carinii pneumonia developed ina control patient 18 months after he received his second cycleof interleukin-2 with indinavir (CD4 count, 12 cells per cubicmillimeter [3 percent]); and lymphoma developed at month 20in the control patient with presumptive toxoplasmosis.
In the interleukin-2 group, the mean CD4 count was maintainedat approximately double the base-line value during the extendedphase of the study (Figure 2). Although the mean values werenot as high as those seen during the controlled phase of thestudy, this difference reflected, at least in part, the individualizationof dosing regimens during the extended phase, which focusedon maintaining CD4 counts above base-line values while decreasingthe frequency of administration of interleukin-2. For the controlpatients, many of whom chose to receive interleukin-2 in theextended phase of the study, there was an increase in CD4 countsafter the initiation of interleukin-2 therapy.
Figure 2. Mean and Median CD4 Counts in the Interleukin-2 and Control Groups during the Controlled and Extended Phases of the Study.
The values shown are based on data for all patients who were available for follow-up, regardless of their status in the study. The numbers at the bottom of the figure indicate the numbers of patients for whom data were available.
Discussion
In this study we have shown that intermittent interleukin-2therapy can lead to substantial and sustained increases in thenumber and percentage of CD4 cells in HIV-infected patientswith base-line CD4 counts of more than 200 cells per cubic millimeter.One year after the beginning of interleukin-2 therapy, the meanCD4 count in the interleukin-2 group was approximately doublethe base-line value. This increase has been sustained for morethan two years by the continued administration of interleukin-2.In five patients, CD4 counts remained above 1000 cells per cubicmillimeter for at least 18 months after interleukin-2 was discontinued.To date, no combination of antiretroviral agents has been shownto be capable of inducing increases in CD4 counts of this magnitudeor duration.
The effects of interleukin-2 in promoting T-cell proliferationlead to a peripheral expansion of mature CD4 T cells, whichmay be maintained by the increase in the expression of CD25(interleukin-2–receptor chain) on these cells. The increasein the number of CD4 cells is unlikely to represent simply theredistribution of cells to the circulation, since there is increasedlymphocyte proliferation as well as lymph-node enlargement duringinterleukin-2 infusions. Moreover, bone marrow biopsies showan increase in lymphoid aggregates, and the increase in somepatients in our study was sustained for more than a year withoutcontinued interleukin-2 therapy.
The effect of intermittent therapy with interleukin-2 was notlimited to CD4 cells. Whereas CD8 counts remained stable, therewas a decrease in the percentage of CD8 cells expressing HLA-DR,a marker of activation (P<0.001). This decrease was onlypartly related to the decline in the total percentage of CD8cells17; it was paralleled by a decrease in the expression ofCD38, another marker of activation (data not shown), and mayreflect the ability of interleukin-2 to enhance CD8 effectorfunction.
A crucial observation in this study is that the administrationof interleukin-2 did not lead to long-term increases in theplasma viral load. Thus, intermittent interleukin-2 therapycan have a substantial impact on the chief immunologic abnormalityassociated with HIV infection, the loss of CD4 T cells, withoutleading to an overall increase in the level of HIV. In the controlgroup, the viral load at study entry was predictive of the netchange in the CD4 count, a finding that highlights the importanceof the plasma viral load as a predictor of future immune status.12,13
The toxicity of interleukin-2 therapy in this study was substantiallylower than that reported in our earlier study, in which a doseof 18 million IU per day was given for a longer portion of thestudy.17 At the mean dose of approximately 8 million IU perday in the latter part of the present study, few dose reductionswere necessary, and substantial immunologic effects were nonethelessseen.
The availability of potent HIV-protease inhibitors has raisedthe hope that sustained suppression of viral replication canbe achieved with combination antiretroviral therapy.4,5,6,7,23Maximal suppression of HIV by such regimens may lead to improvedCD4 responses to interleukin-2 therapy. Preliminary experiencewith intermittent interleukin-2 plus indinavir, a recently approvedprotease inhibitor, suggests that responses to interleukin-2are enhanced when there is profound suppression of viral replication.24Complementing antiretroviral therapy with interleukin-2 is anattractive approach. Since interleukin-2 targets the immunesystem rather than the virus, alterations in the viral genomeshould not lead to resistance to the effects of interleukin-2on CD4 cells. Indeed, some patients have continued to respondto interleukin-2 therapy for more than 50 months (unpublisheddata).
Although interleukin-2 can have a profound and sustained effecton CD4 counts in HIV-infected patients with base-line CD4 countsabove 200 cells per cubic millimeter, the long-term clinicalbenefits of this increase remain to be established.
We are indebted to the patients and their referring physiciansfor their willingness to participate in and support the study;to the members of the data and safety monitoring board for theirtime, effort, and helpful recommendations; to the staff of theNIAID inpatient unit and the outpatient research clinic of theNIAID and Critical Care Medicine Department; to Mary A. Foulkesfor her help in designing and evaluating the study; and to AnthonyS. Fauci for his support and guidance.
Source Information
From the Critical Care Medicine Department, Clinical Center (J.A.K.), the Laboratory of Immunoregulation (S.V., J.F., R.T.D., R.E.W., M.A.P., K.S., J.A.M., H.C.L.), and the Division of AIDS (J.M.A.), National Institute of Allergy and Infectious Diseases, Bethesda, Md.; Science Applications International Corporation, Frederick, Md. (M.B.); and Chiron Corporation, Emeryville, Calif. (G.F.). Other authors were Robin J. Dewar, Ph.D., Science Applications International Corporation, Frederick, Md.; and Henry Masur, M.D., Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Md.The U.S. government has been issued a patent for immunologic enhancement with intermittent interleukin-2 therapy, listing Drs. Kovacs and Lane as inventors.
Address reprint requests to Dr. Kovacs at Bldg. 10, Rm. 7D43, MSC 1662, National Institutes of Health, Bethesda, MD 20892-1662.
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chain) on these cells. The increase in the number of CD4 cells is unlikely to represent simply the redistribution of cells to the circulation, since there is increased lymphocyte proliferation as well as lymph-node enlargement during interleukin-2 infusions. Moreover, bone marrow biopsies show an increase in lymphoid aggregates, and the increase in some patients in our study was sustained for more than a year without continued interleukin-2 therapy. 
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