Filgrastim prevents severe neutropenia and reduces

infective morbidity in patients with advanced HIV

infection: results of a randomized, multicenter,
controlled trial
Daniel R. Kuritzkes, David Parenti*, Douglas J. Ward, Anita Rachlis,
Roberta J. Wong, Kenneth P. Mallon, William J. Rich,
Mark A. Jacobson and the G-CSF 930101 Study Group**
Objective: To assess the effect of filgrastim treatment on the incidence of severe
neutropenia in patients with advanced HIV infection, and the effect of initial
filgrastim treatment on prevention of infectious morbidity.
Design: Randomized, controlled, open-label, multicenter study.
Setting: Outpatient centers and physician offices.
Patients: Men and women aged > 13 years, who were HIV antibody-positive, and had
a CD4 cell count < 200 106/l, absolute neutrophil count (ANC) 0.751.0 109/l,
and platelet count 50 109/l within 7 days of randomization were eligible. Two
hundred and fifty-eight patients entered and 201 completed the study.
Intervention: Daily filgrastim (starting at 1 g/kg daily, adjusted up to 10 g/kg daily)
or intermittent filgrastim (starting at 300 g daily one to three times per week to a
maximum of 600 g daily 7 days weekly) was administered to maintain an ANC
between 2 and 10 109/l. Patients in the control group received filgrastim if severe
neutropenia developed.
Main outcome measures: Incidence of severe neutropenia (ANC < 0.5 109/l) or
death, incidence of bacterial and fungal infections, duration of hospitalization and
intravenous antibacterial use, and safety.
Results: The primary endpoint of severe neutropenia or death was less frequent in
patients who received daily (12.8%) or intermittent (8.2%) filgrastim compared with
control patients (34.1%; P < 0.002 and P < 0.0001 for comparison with daily and
intermittent groups, respectively). Filgrastim-treated patients developed 31% fewer
bacterial infections and 54% fewer severe bacterial infections than control patients,
required 26% less hospital days including 45% fewer hospital days for bacterial
infections, and needed 28% fewer days of intravenous antibacterials. Filgrastim was
not associated with an increase in HIV-1 plasma RNA level in a subset of patients in
whom this was measured or any new or unexpected adverse events.
Conclusion: Filgrastim was safe and effective in preventing severe neutropenia in
patients with advanced HIV infection, and may reduce the incidence and duration
of bacterial infections, incidence of severe bacterial infections, duration of hospital
days for infections, and days of intravenous antibacterial agents.

AIDS 1998, 12:6574

Keywords: AIDS, bacterial infection, hematology, hematopoietic growth factors,

hospitalization, neutropenia, outpatient, randomized study

From the University of Colorado Health Sciences Center, Denver, Colorado, the *George Washington University, the

Dupont Circle Physicians Group, Washington, DC, USA, the Sunnybrook Health Sciences Center, University of Toronto,
Toronto, Canada, Amgen Inc., Thousand Oaks, and the University of California San Francisco and San Francisco General
Hospital, San Francisco, California, USA. **See Appendix.
Sponsorship: This study was supported by Amgen Inc., Thousand Oaks, California, USA.
Requests for reprints to: Dr Daniel R. Kuritzkes, University of Colorado Health Sciences Center, Division of Infectious
Diseases, 4200 East 9th Avenue, B168, Denver CO 80262, USA.
Date of receipt: 28 May 1997; revised: 10 September 1997; accepted: 15 September 1997.

Rapid Science Publishers ISSN 0269-9370 65

66 AIDS 1998, Vol 12 No 1
Introduction
Neutropenia is common in patients with advanced
HIV infection [1]. The causes of neutropenia in HIV
infection vary, but are primarily due to impaired
hematopoiesis resulting from several factors, including
the use of myelotoxic agents directed against HIV and
opportunistic pathogens [2,3], direct infection or infil-
tration of bone marrow by HIV, secondary infections
or neoplasms [46], apoptotic death of uninfected
hematopoietic progenitor cells and more mature cells
[7], nutritional deficiency [8], and antibodies directed
against bone-marrow progenitor cells [9].
Several studies have shown that neutropenia is an inde-
pendent risk factor for bacterial infection in patients
with HIV disease [1015]. In addition, neutropenia
may also complicate the use of myelosuppressive ther-
apy in HIV-infected patients. Zidovudine, ganciclovir,
and trimethoprimsulfamethoxazole (TMP-SMX) are
first-line treatments for HIV disease and related oppor-
tunistic infections [16,17] and can cause neutropenia.
Treatment interruption or discontinuation because of
medication-induced neutropenia may lead to subopti-
mal treatment and disease progression [18,19].
Recombinant methionyl human granulocyte colony-
stimulating factor (r-metHuG-CSF, filgrastim) is a bac-
terially synthesized recombinant protein that increases
the production of neutrophils by stimulating prolifera-
tion and differentiation of neutrophil progenitors
[2022]. Filgrastim increases absolute neutrophil count
(ANC) and enhances the phagocytic and bactericidal
functions of neutrophils [23]. Several uncontrolled pilot
studies have shown that filgrastim increases ANC in
neutropenic patients with HIV infection [2429].
We therefore performed a randomized, controlled trial
to assess the safety and efficacy of filgrastim using doses
most often prescribed in clinical practice in preventing
severe neutropenia (ANC < 0.5 10 9 /l) in HIV-
infected patients. In addition, we assessed the rate and
duration of bacterial and fungal infections, duration of
hospitalization and intravenous antibacterial use, and
safety.
Material and methods
Study population
The study protocol was reviewed and approved by the
appropriate institutional review boards, and all patients
gave written informed consent before study entry.
Individuals aged > 13 years with documented HIV
infection (antibody-positive by enzyme-linked
immunosorbent assay, confirmed by Western blot
analysis or indirect immunofluorescence assay) were
eligible for study if they had an ANC 0.75 but
< 1.0 109/l less than 7 days before randomization. In
addition, patients were required to have a CD4+ lym-
phocyte count 200 106/l, platelet count > 50
109/l, Karnofsky performance score >50%, and life
expectancy 6 months. Dosages of any antiretroviral
agent (e.g., zidovudine, didanosine, zalcitabine, or
stavudine), and TMP-SMX, interferon-, and ampho-
tericin B were kept constant for at least 14 days before
randomization. Patients could be enrolled after ganci-
clovir induction therapy for cytomegalovirus retinitis
and were required to be on a stable maintenance dose
of ganciclovir for 2 weeks before randomization.
Patients were excluded if they had a malignancy (with
the exception of stable Kaposis sarcoma not requiring
systemic treatment with myelosuppressive therapy, or
localized basal or squamous cell carcinoma), known
hypersensitivity to Escherichia coli-derived products,
treatment with filgrastim or other hematopoietic
growth factors (with the exception of erythropoietin)
within 14 days of randomization, or if they were
pregnant or breastfeeding. Use of investigational anti-
retroviral agents was permitted with prior approval
from the sponsor.
Study design and treatment regimen
The study was a 24-week, multicenter, open-label,
randomized controlled trial. Patients were randomized
to receive daily or intermittent subcutaneous doses of
filgrastim, or to an observational control group in a
ratio of 1 : 1 : 1. Filgrastim (r-metHuG-CSF; Amgen,
Inc., Thousand Oaks, California, USA) was provided
in 1 ml vials containing 0.3 mg/ml for self-injection.
Filgrastim dosage in both treatment groups was titrated
to maintain an ANC of 210 109/l. For patients in
the daily treatment group, filgrastim dosage started at
1 g/kg daily, and could be increased to a maximum of
10 g/kg daily; for patients in the intermittent treat-
ment group, filgrastim dosage started at 300 g daily
one to three times per week, and could be increased to
a maximum of 600 g daily. Study drug was discontin-
ued in the event of a serious adverse event deemed to
be possibly, probably, or definitely related to its admin-
istration, or a white blood cell count 75 109/l at the
24 h nadir after drug administration. Patients in the
control group who developed severe neutropenia were
re-randomized to receive filgrastim according to the
regimen of one of the two treatment groups for the
remainder of the 24-week study period.
Patients continued to receive conventional treatment
for HIV at the discretion of their physicians.
Neutrophil counts were monitored three times weekly
for the first 2 weeks, and weekly thereafter. Regardless
of treatment group assignment, investigators made
adjustments to myelosuppressive drugs on the basis of
clinically significant changes in hematologic variables
according to the patients medical status and the stan-
 Prevention of severe neutropenia by filgrastim in HIV Kuritzkes et al.
dards of clinical practice. Adjustments were not allowed
during the confirmation of severe neutropenia.
Primary study endpoints
The primary endpoint for this study was the occur-
rence of confirmed severe neutropenia or death during
the 24-week study period. A confirmed episode of
severe neutropenia was defined as two consecutive
ANC measurements < 0.5 10 9 /l obtained within
7 days, but at least 24 h apart.
Secondary study endpoints
Secondary endpoints included incidence of microbial
infections (bacterial and fungal), incidence of severe
microbial infections, days of hospitalization, days of
hospitalization for bacterial infections, use of myelosup-
pressive therapy, and days of intravenous antibacterial
therapy.
Microbial infections
All presumptive and definitive diagnoses of microbial
infection were included in the analyses. For definitive
diagnosis, bacterial infections were confirmed by cul-
ture with the exception of pneumonia and sinusitis.
Diagnosis of bacterial pneumonia required presence of
a new infiltrate on chest radiograph, and at least one of
the following: diagnostic sputum Gram stain, or
positive culture of a respiratory pathogen from bron-
choalveolar lavage fluid or protected brush specimen.
Fungal infections were confirmed by culture or biopsy.
The incidence of sinusitis was tabulated, but not
included in the analysis of bacterial infections because
of the difficulty in distinguishing bacterial from non-
bacterial forms of sinusitis in HIV-infected patients. In
the absence of confirmatory evidence, a presumptive
diagnosis of bacterial or fungal infection could be made
on the basis of a compatible clinical syndrome. The
severity of bacterial infections was determined by the
investigators and was graded as mild, moderate, severe,
or life-threatening.
Hospitalizations
Days of hospitalization for all causes were counted by
using admission and discharge dates. The number of
days that each hospitalization was prolonged because of
bacterial infections was also recorded.
Myelosuppressive and antibacterial therapy
For the analysis of myelosuppressive medications, full,
high and reduced doses of ganciclovir, zidovudine, and
TMP-SMX doses were defined. Ganciclovir doses
were categorized as reduced if < 75% of the standard
dose (5 mg/kg intravenously daily equivalent to
1000 mg orally three times daily), full if 75150%, and
high if 150%. Similarly, zidovudine was classified
as reduced for < 500 mg daily doses, full for August 1995. Patients in the three groups were compa-
500600 mg daily doses, and high for doses over 600
mg daily. For TMP-SMX, doses < 600 mg daily were
67
considered reduced, doses 6001000 mg daily were
considered full, and doses 1000 mg daily were con-
sidered high (based on the trimethoprim component).
All doses were categorized in a blinded fashion. This
allowed the calculation of days of full- and high-dose
myelosuppressive medication use.
Statistical analysis
All analyses were performed on an intention-to-treat
basis. The primary efficacy analysis was based on a
comparison of daily filgrastim treatment versus control,
and intermittent filgrastim versus control. An additional
analysis of the combined groups was performed due to
similarities in the treatment effects. The percentage of
patients who reached the primary endpoint in each
group was estimated by the KaplanMeier method.
The t test was used to compare the difference in per-
centages, calculating the variance of the difference
using Greenwoods formula [30].
All incidence rates were reported as number of events
per 1000 patient-days. The number of events that
occurred from the day of randomization to the day of
study termination (or study day 168, whichever came
first) were counted for each patient. These totals were
converted to incidence rates by dividing the total num-
ber of events in each treatment group by the total
number of at-risk days for each treatment group.
Generalized linear models were used to calculate the
variances of the point estimates to allow for hypothesis
testing. This quasi-likelihood model used a logarithmic
link function, which was adjusted for differential obser-
vation time using an offset term, and was based on the
assumption that the underlying mean was proportional
to the variance.
Safety
Safety was assessed through periodic clinical and labora-
tory determinations beginning at date of randomization
and continuing through week 24, or death (if earlier).
Deaths that occurred up to 30 days after study termina-
tion were recorded. Plasma HIV-1 RNA levels were
measured by quantitative reverse transcriptase poly-
merase chain reaction (National Genetics Institute,
Culver City, California, USA) on a subset of patients at
baseline, and at weeks 12 and 24. CD4+ cell counts
were obtained from all patients.
Results
Patient population
A total of 258 patients at 30 centers in the United
States and Canada were randomized from July 1993 to
rable at baseline with respect to both demographic and
clinical characteristics (Table 1). Patients for whom the
68 AIDS 1998, Vol 12 No 1

Table 1. Patient characteristics at baseline.

Daily dosing Intermittent dosing Control
(n = 83) (n = 89) (n = 86)
Mean (range) age (years) 39.7 (2365) 39.3 (2566) 40.3 (2060)
Sex [n (%)]
Female 9 (11) 6 (7) 8 (9)
Ethnicity [n (%)]
Non-white 18 (22) 21(24) 24 (29)
Median (range)
ANC ( 109/l) 0.9 (0.5001.846) 0.9 (0.1362.112) 0.9 (0.4732.546)
CD4+ cell count ( 106/l) 14 (0180) 12 (0186) 20 (0185)
Prior opportunistic infections 3 (016) 4 (020) 3 (010)
lndwelling catheters [n (%)]
Yes 21 (25.3) 22 (24.7) 25 (29.1)
Medications (%)
TMP-SMX 67.5 62.9 61.6
Rifabutin 31.3 30.3 19.8
Clarithromycin 19.3 25.8 24.4
Zidovudine 36.1 38.2 33.7
Ganciclovir 22.9 21.3 22.1
ANC, Absolute neutrophil count; TMP-SMX, trimethoprimsulfamethoxazole.

date of HIV infection could be estimated reported a was 147, 158, and 139 days on study, respectively.
median duration of 3.8 years. The median ANC at the Fifty-seven patients (22.1%) withdrew from the study
time of randomization was 0.9 10 9 /l (range, prematurely (before week 24). The most common rea-
0.1362.546 109/l). The median CD4 cell counts for sons for withdrawal was patient or investigator decision
all patients was 15 106/l (range, 0186 106 cells/l; (22 patients), an adverse event (six patients), or death
Table 1). The median number of prior opportunistic (13 patients). Overall, reasons for early withdrawal
infections was similar in the three groups, with the were balanced amongst all three groups.
intermittent filgrastim-treated group having the greatest
number of prior opportunistic infections. Filgrastim effect on neutrophil count
Patients receiving filgrastim had a prompt and sustained
Approximately 80% of patients were receiving antibac- increase in ANC (Fig. 1). The median time to reversal
terial agents at study entry. The most frequently used of neutropenia was 3 days in the daily treatment group
antibiotics were TMP-SMX (64%), rifabutin (27.1%), and 8 days in the intermittent treatment group. The
and clarithromycin (23.3%). Use of TMP-SMX was slight increase in mean ANC observed in the control
similar in all three groups. Rifabutin use was greater in group was attributable to the 18 patients who received
both filgrastim treatment groups compared with the filgrastim after crossing over to filgrastim treatment.
control group, whereas clarithromycin use was more
common in the intermittent filgrastim and control
groups than in the daily filgrastim group (Table 1).
Approximately 70% of patients were receiving antifun-
gal medications and 8090% were using antiviral
agents. More than 50% of the patients were receiving
fluconazole, and approximately 20% were receiving
ganciclovir at study entry. Use of these medications was
evenly balanced amongst the three groups.
Suspected causes of neutropenia for patients enrolling
into the study were multifactorial. Investigators attrib-
uted neutropenia, at least in part, to HIV infection in
89.5% of the patients. Additional contributory factors
included antiretroviral therapy (53.9%), other
myelosuppressive therapy (37.6%), and opportunistic
infection (11.6%).
Patient disposition
All patients in the filgrastim-treated groups received at Fig. 1. Mean absolute neutrophil count (ANC) at weeks
least one dose of filgrastim. Average follow-up for 124. (M), Daily filgrastim dosing (n = 83); (), intermittent
patients in the daily, intermittent, and control groups filgrastim dosing (n = 89); (j), controls (n = 86).
 Prevention of severe neutropenia by filgrastim in HIV Kuritzkes et al. 69

Table 2. Primary endpoint results.
n (%)*
Daily Intermittent Control
dosing dosing
Event (n = 83) (n = 89)
Confirmed severe neutropenia
or death 10 (12.8) 7 (8.2)
Confirmed severe neutropenia 1 (1.2) 2 (2.2)
Death 9 (10.8) 6 (6.7)
*Percentages based on KaplanMeier estimates. P < 0.002 versus
control (t-test applied to KaplanMeier estimates). P < 0.0001
versus control (t-test applied to KaplanMeier estimates).
The crossover of these 18 patients was evenly distrib-
uted throughout the 24-week study period. Patients in
the daily filgrastim treatment group who were able to
reverse their neutropenia required a mean of 1.2 g/kg
daily to maintain ANC 2 109/l; those receiving
intermittent dosing of filgrastim required a mean of
two 300 g doses per week.
Primary study endpoint
Filgrastim significantly reduced the occurrence of the
primary endpoint (confirmed severe neutropenia or
death; Table 2). Summaries of the individual compo-
nents of this composite endpoint indicated that the
effect of filgrastim on the primary endpoint was
primarily due to differences observed in the incidence
of confirmed severe neutropenia, because death rates,
although slightly lower in filgrastim-treated groups,
were comparable across all groups.
Secondary study endpoints
Microbial infections
Eighty-five patients developed a total of 128 new or
worsening bacterial infections during the study period.
The most common bacterial infections included
Mycobacterium avium infection (n = 27), pneumonia
(n = 14), catheter-related infections (n = 13), cellulitis
(n = 12), and gastrointestinal infections (n = 11). The
most frequently isolated microorganisms were M. avium
complex (MAC), streptococci, Klebsiella pneumoniae,
group and Pseudomonas aeruginosa. MAC was the most com-
(n = 86) mon cause of severe infection in all treatment groups.
26 (34.1) Both daily and intermittent dosing with filgrastim low-
19 (22.1) ered the incidence of bacterial infections compared
10 (11.6)
with the control group (Table 3, Fig. 2). Overall, fil-
grastim-treated patients developed 31% fewer bacterial
infections than patients in the control group (P = 0.07).
The magnitude of this effect was similar in analyses that
adjusted for CD4+ lymphocyte count and number of
prior opportunistic infections and the results did not
depend on baseline concomitant medication use. The
effect of filgrastim among patients receiving zidovudine
[relative risk (RR), 0.63] was similar to those not
receiving zidovudine (RR, 0.73). Patients receiving
ganciclovir (RR, 0.72) or not receiving ganciclovir
(RR, 0.69) had similar effects of filgrastim treatment.
Likewise, filgrastim treatment resulted in statistically
significant reductions in the risk of severe bacterial
infections (relative hazard for combined treatment
groups versus control, 0.46; P = 0.005). Treatment
with filgrastim did not alter the incidence of fungal
infections in this study (4.14 per 1000 patient-days in
the treated groups versus 4.50 per 1000 patient-days in
the control group).
Although rifabutin use was seen to be greater in the fil-
grastim-treated patients at study entry, analyses that
adjusted for rifabutin use did not change the results.
Hospitalizations
Filgrastim-treated patients spent fewer days in the hos-
pital than control patients. The overall effect of filgras-
tim on hospitalization days was not statistically
significant; however, its effect on reducing days of hos-

Table 3. Relative risk (RR) of various outcomes for all filgrastim-treated patients versus control patients.
Unadjusted Adjusted*
RR (95% CI) P RR (95% CI) P
Bacterial infection
Daily 0.67 (0.411.11) 0.12 0.66 (0.401.07) 0.09
Intermittent 0.70 (0.441.13) 0.14 0.64 (0.411.23) 0.06
Combined 0.69 (0.461.03) 0.07 0.65 (0.300.97) 0.03
Severe bacterial infection
Daily 0.60 (0.301.20) 0.15 0.59 (0.301.16) 0.13
Intermittent 0.33 (0.160.68) 0.003 0.29 (0.140.60) 0.0008
Combined 0.46 (0.260.79) 0.005 0.43 (0.250.74) 0.002
Hospital days
Daily 0.72 (0.421.24) 0.24 0.70 (0.411.19) 0.19
Intermittent 0.76 (0.451.28) 0.31 0.70 (0.421.16) 0.17
Combined 0.74 (0.471.16) 0.19 0.70 (0.451.07) 0.10
Bacterial infection-related hospital days
Daily 0.51 (0.231.11) 0.09 0.50 (0.231.09) 0.08
Intermittent 0.58 (0.281.22) 0.15 0.53 (0.251.09) 0.09
Combined 0.55 (0.301.00) 0.05 0.51 (0.280.92) 0.03
*Baseline CD4 cell count and number of prior opportunistic infections. CI, Confidence interval.
70 AIDS 1998, Vol 12 No 1

(a) (b)

(c) (d)

Fig. 2. (a) Incidence of bacterial infections, all patients. (b) Bacterial infection days, all patients. (c) Hospital days, all patients.
(d) Hospital days due to bacterial infections, all patients. (M), Daily filgrastim group (n = 83); ( ), intermittent filgrastim group
(n = 89); ( ), all filgrastim-treated patients combined (n = 172); (m), control patients (n = 86).

pitalization for bacterial infections (Table 3, Fig. 2)
appeared stronger. This result suggests that the reduc-
tion in hospital days overall was primarily due to the
specific effect of filgrastim on the incidence of bacterial
infections.
Myelosuppressive and intravenous antibiotic therapy
Ninety-eight of the 258 (38%) patients were taking
two or more myelosuppressive drugs (including ganci-
clovir, zidovudine, and TMP-SMX) at study entry. Six
(20%) out of 30 control group patients and none of the
68 filgrastim-treated patients taking two or more of
these agents became severely neutropenic. Seven out of
18 control group patients who were receiving ganci-
clovir at study entry became severely neutropenic,
compared with none of the 39 filgrastim-treated
patients receiving ganciclovir at study entry
(P = 0.0001). Patients in filgrastim-treated groups
received 12% more days of full-dose or high-dose
myelosuppressive medications in filgrastim-treated
groups compared with the control group (data not
shown). This increase was observed with the near
absence of severe neutropenia. In addition, patients in
the filgrastim-treated groups required 28% fewer days
of intravenous antibacterial use than patients in the
control group.
Safety
All randomized patients were evaluable for safety assess-
ments. At least one adverse event was reported by
98.3% of filgrastim-treated patients and 94.2% of con-
trol group patients. The most frequently reported
adverse events were fever, diarrhea, fatigue, nausea,
headache, anemia, abdominal pain, vomiting, and
myalgia. Overall, there were no unexpected clinically
significant differences in adverse events in the three
 Prevention of severe neutropenia by filgrastim in HIV Kuritzkes et al.
Fig. 3. Change in log10 plasma HIV-1 RNA titer from base-
line to week 24.
patient groups. At least one severe adverse event was
reported by 39.5% of filgrastim-treated patients and
44.2% of control patients. The most common severe
adverse events were thrombocytopenia and anemia.
Severe thrombocytopenia occurred in 12 (7.0%) out of
172 filgrastim-treated patients and in three (3.5%) out
of 86 control patients. The incidence of severe anemia
was similar in all groups.
Filgrastim treatment was not associated with an increase
in plasma HIV-1 RNA levels over 24 weeks in the
subset of patients in whom this was tested (Fig. 3). In
addition, there was no effect of filgrastim on CD4+
lymphocyte count.
Discussion
This study shows that filgrastim was safe and effective
in preventing severe neutropenia in patients with
advanced HIV disease and mild neutropenia (ANC
0.751.0 10 9 /l). Administering filgrastim when
patients are mildly neutropenic rather than waiting for
patients to become severely neutropenic (as in our con-
trol group) was associated with reduction in the inci-
dence of bacterial infections, including serious bacterial
infections, and reduction in days of hospitalization for
bacterial infection in patients. Trends toward reduced
use of intravenous antibacterial medications as well as
increased use of myelosuppressive agents in the filgras-
tim-treated group were also seen. These results suggest
that use of filgrastim to maintain a normal neutrophil
count confers important clinical benefits in patients
with advanced HIV disease.
In this study, a median daily filgrastim dose of 1 g/kg
daily or two 300 g doses per week were required to
maintain an ANC of 210 10 9 /l. Similar dose
requirements were reported in a non-controlled study
of filgrastim in 200 HIV-infected patients with ANC
71
< 1.0 109/l [31]. In that study, filgrastim reversed
neutropenia in 98% of patients with a median daily
dose of 1.0 g/kg during the initial treatment phase.
During the maintenance phase, a median of three 300
g doses per week were required to maintain an ANC
of 25 109/l. These doses are substantially lower than
the median dose required in the oncology setting. As in
the previous report [31], patients who received filgras-
tim in the present study were better able to tolerate
administration of myelosuppressive medications,
including zidovudine, TMP-SMX, and ganciclovir.
The beneficial effects of filgrastim on neutrophil func-
tion are multifactorial. In vitro studies with purified
neutrophils have demonstrated that filgrastim increases
respiratory burst and phagocytic activity, and improves
bacterial cell killing [23,32]. Each of these functions is
greater in recently produced neutrophils.
Administration of filgrastim to humans increases the
rate of neutrophil production, resulting in the release of
large numbers of young neutrophils. It is possible that
the clinical benefits of filgrastim seen in the setting of
advanced HIV disease are due not only to the increase
in neutrophil number, but also to an intrinsic improve-
ment in neutrophil function.
Previous studies have shown that the risk of bacterial
infection in HIV-infected individuals increases with
decreasing neutrophil count [11,15]. This risk is great-
est among patients with severe neutropenia (< 0.5
109/l). Because of concerns for the safety of patients in
the control group, this study included a cross-over
design that provided filgrastim treatment to subjects
who developed severe neutropenia. The effect of this
design was to limit the power of the study to detect sta-
tistically significant differences between treatment
groups with regard to the secondary endpoints. Patients
were limited to the extent of their neutropenia because
their physicians acted quickly to cross them over to
filgrastim treatment. Nevertheless, a consistently favor-
able effect of filgrastim on the incidence of a variety of
secondary endpoints was observed.
Another consequence of the study design was the low
incidence of bacterial and fungal infections overall. The
rate of bacterial infections in the control group was
4.25 per 1000 patient-days. This rate was reduced to
2.93 per 1000 patient-days in the combined filgrastim-
treated groups. It is likely that the rate of bacterial
infections in the control group would have been even
higher if we had allowed the ANC to decrease to
< 0.5 109/l for extended periods of time. Evidence
from previous studies suggests that filgrastim is highly
effective in correcting neutropenia in this group of
patients [28,29,31]. Thus, the clinical benefit observed
in the present study may be taken as a minimum esti-
mate of the efficacy of filgrastim at preventing bacterial
infections in patients with more serious degrees of neu-
72 AIDS 1998, Vol 12 No 1
tropenia. Because assignment to treatment group was
not blinded, the potential for bias existed in the diag-
nosis of bacterial infections and grading the severity of
these infections. This concern may be partially allayed
since 55% of bacterial infections were microbiologically
confirmed.
Another study has shown that use of antimicrobial
agents such as TMP-SMX significantly reduce the risk
of bacterial infection in patients with HIV disease [33].
In this study, use of TMP-SMX significantly reduced
the risk of bacterial infection by nearly twofold.
However, statistical adjustment for TMP-SMX use did
not change the results.
Use of macrolides or rifamycins for prevention of dis-
seminated infection due to MAC might also contribute
to a reduction in bacterial infections in addition to
reducing the incidence of MAC. At the time this study
began, MAC prophylaxis was not yet routinely recom-
mended for patients with advanced HIV disease.
Although rifabutin use increased over the time of the
study, only 40% of patients received prophylactic
rifabutin. Since disseminated MAC infections consti-
tuted a significant number of the bacterial infections
observed, it is possible that wider use of MAC prophy-
laxis might reduce the differences in rates of infection
between the filgrastim and control groups.
Patients receiving filgrastim spent fewer days in the
hospital overall, and had significantly fewer days of
hospitalization for bacterial infection. There was also a
trend toward less frequent use of intravenous antibacte-
rial agents. Although a formal pharmaco-economic
analysis has not been carried out, treatment that reduces
the incidence of serious bacterial infections and reduces
days of hospitalization is likely to have a substantial
economic impact on the management of patients with
advanced HIV disease.
Changes in the management of HIV infection brought
about by the availability of more potent antiretroviral
agents and improvements in the management and pre-
vention of opportunistic infections may reduce the
incidence of neutropenia among HIV-infected individ-
uals. For those patients who do develop neutropenia,
results of this study suggest that filgrastim was safe and
effective in preventing severe neutropenia and its com-
plications in patients with advanced HIV disease. The
results of the study indicate the clinical benefit of treat-
ing mildly neutropenic patients rather than waiting
until severe neutropenia occurs. Additional studies are
needed to define the optimum strategy for use of
filgrastim in HIV-infected patients and to address the
role, if any, of filgrastim as adjuvant therapy for specific
bacterial or fungal infections.
Acknowledgement
The authors thank M.A. Foote for assisting in the
preparation of the manuscript.
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Appendix
Members of the G-CSF 930101 Study Group
Ronald Mitsuyasu, MD, and Susie McCarthy, RN
(UCLA Care Center, Los Angeles, California); Harold
Kessler, MD, and Michelle M. Agnoli, RN, BSN
(Infectious Disease Outpatient Clinic, Rush
PresbyterianSt Lukes Medical Center, Chicago,
Illinois); Gary Simon, MD, PhD, and Suzanne Schuck,
RN, BSN (George Washington University Medical
Center, Washington, DC); Kathleen E. Squires, MD,
and Donna David, RN (University of Alabama at
Birmingham, Birmingham, Alabama); Steve Johnson,
MD, and M. Graham Ray, MSN (University of
Colorado Health Sciences Center, Denver, Colorado);
David T. Scadden, MD (at time of study: New
England Deaconess Hospital, Boston, Massachusetts);
Jack Fuhrer, MD, and Christine Wallace, MS, RN
73
(University Hospital, State University of New York at
Stony Brook, Stony Brook, New York); Michael
Lederman, MD, and John T. Carey, MD (University
Hospital of Cleveland, Cleveland, Ohio); Mary Payne,
MD (University of California San Francisco, San
Fransisco, California); Rebecca Coleman, PharmD (San
Francisco General Hospital, San Francisco, California);
Diane Antoniskis, MD, and Mark Rarick, MD (Kaiser
Permanente Immune Deficiency Clinic, Portland,
Oregon); Michael Lobell, MD (Maricopa Medical
Center, Oncology Clinic, Phoenix, Arizona); John
Post, MD (McDowell Health Care Clinic, ID, HIV,
and AIDS Clinic, Phoenix, Arizona); Mary Fanning,
MD, and Corina Ouan, MD (Wellesley Central
Hospital, Toronto, Canada); Julie Phillips, BSN, and
Linda Moran, RN (Sunnybrook Health Sciences
Centre, Toronto, Canada); Peter Phillips, MD (St
Pauls Hospital, Vancouver, British Columbia);
Raymond Beaulieu, MD, FRCPC, and Emil Toma,
MD (Hotel-Dieu de Montreal, Montreal, Canada);
Joseph Jemsek, MD, and Jan Caldwell, LPN (Nalle
Clinic, Charlotte, North Carolina); Anthony Lamarca,
MD, and Denise Lamarca, MBA (Therafirst Medical
Center, Ft Lauderdale, Florida); Donna E. Sweet, MD,
FACP, and Dairone E. Harrison, RN (University of
Kansas Medical School Wichita, Wichita, Kansas);
Patricia K. Sharkey, MD, and Michelle Britton
(Immuno-Suppression Clinic, San Antonio, Texas);
Newton Hyslop Jr, MD, and David Mushatt,
MD/MPA (Medical Center of Louisiana at New
Orleans, General Clinic Research Center, New
Orleans, Lousiana); Kent Sepkowitz, MD (The New
York Hospital, Cornell University, New York, New
York); Tricia Sarracco, RN (Cornell Clinic Trials
Unit, New York, New York); Ellen S. Yetzer, DO,
and Donna S. Morales, RN (Pacific Oaks Research,
Beverly Hills, California); Donald Craven, MD, and
Lisa Hirschhorn, MD, MPH (Boston City Hospital, ID
Research Clinic, Boston, Massachusetts); Perry Pate,
MD, and Steven G. Davis, MD (ID Associates, Dallas,
Texas); C. Kenneth McAllister, MD, and LTC David
Dooley, MD (Brooke Army Medical Center, Ft Sam
Houston, Texas); Peter Hawley, MD, and Christiane
Jones, RN (Whitman-Walker Clinic, Inc.,
Washington, DC); Gary Blick, MD, and Una Hopkins,
RN, MSN (Blick Medical Associates, Greenwich,
Connecticut); Douglas Dieterich, MD, and Kathleen
Farrel, RN (NYU Medical Center, New York, New
York); Samuel Golden, MD, and Roger Anderson,
MD (Braddock Medical Center, Pittsburgh,
Pennsylvania); P. Samuel Pegram, MD (Bowman Gray
School of Medicine, Winston-Salem, North Carolina);
John K. Gartling, PA (Department of Internal
Medicine/Section of Infectious Diseases, Winston-
Salem, North Carolina); Shannon Schrader, MD, and
Patrick McNamara, MD (Houston Clinical Research
Network, Division of Montrose Clinic, Houston,
74 AIDS 1998, Vol 12 No 1

Texas); Douglas J. Ward, MD (Dupont Circle Programme, London, Ontario, Canada); Mallory Witt,
Physicians Group, Washington, DC); Ian Mackie, MD, MD, and Crystal Lane, RN (Harbor-UCLA Medical
FRCPC (St Josephs Health Centre, London, Ontario, Center, Torrance, California); Pamela C. Ventra, MD,
Canada); Janet Gilmour, MD, FRCPC (HIV Care MA (Novum, Inc., Pittsburgh, Pennsylvania).