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An Association Between Clotting Factor Concentrates Use and Mortality in
Human Immunodeficiency Virus-Infected Hemophilic Patients
BY J O S ~B. Montoro, Juan Oliveras, J. lgnacio Lorenzo, Joan M. Tusell, Carmen Altisent, Rafael Molina,
and Ana I. Ayestaren
Thereismuchevidence that clotting factor concentrates
(CFC), especially the so-called intermediate-purity preparations, exert an immunomodulating effect
in vitro. The impact
of this effect on the outcome of human immunodeficiency
virus (HN) infection in hemophiliacs is still controversial.
In
this retrospective cohort study,
the effects oftreatment with
CFC on mortality and progressionto acquired immunodeficiency syndrome (AIDS) were estimated while controlling
for individual risk factors. Logistic regredon and survival
analysis, including the Cox proportional-hazards regression
1
follow-up
model, were performed with data from a l-year
of 225 hemophilic patients seropositive for HIV
type 1 (HIV1) of two hemophilia centers. Mortalii and progression to
AIDS rates were strongly associated with lower administra-
tion of CFC. After adjusting for age,
a statistically signifcant
and robust association was observed. The use of CH: was
negatively associated with progression to AIDS ( P = .0252)
and mortalii (P = .0033). The adjusted relative hazardsof
mortality and progression to AIDS rate between the most
treated patients (>700 IU/kg/yr) versus the least treated
(5700 IU/kg/yr) were 0.53 (confidence limits, 0.33 to 0.86)
and 0.57 (0.39 to 0.84). respectively. Although the effects
of other unmeasured risk factors cannot be excluded with
certainty, these results suggest
that there is a negative
association between treatment with CFC andprogression to
AIDS and mortality.
0 1995 by The American Societyof Hematology.
I
de Hemofilia, Hospital Vall d’Hebron [Barcelona] and Centro de
Coagulopatias, Hospital la Fe [Valencia]) were selected. Of the 259
patients initially followed-up, 4 were excluded because they belonged to another risk population (3 drug abusers and l homosexual)
and 7 were excluded because of death not related to HIV (6 for
central nervous system [CNSI-related bleeding and 1 gastrointestinal-related bleeding). Of the remaining 248 patients, 23 were lost
for control in the follow-up. Finally, 225 patients were included
in the cohort. Demographic characteristics of the selected patients
included in the cohort are summarized in Table 1.
All patients had received treatment with CFC before 1983, so in
the absence of other risk factors, it is assumed that seroconversion
to HIV infection was directly related to these concentrates. The year
taken for seroconversion to HIV was 1982 because 1982 is considered to have the highest hazard of HIV infection in hemophiliacs,
according to recent epidemiologic studies.”.” Seropositivity to HIV
was determined by enzyme-linked immunosorbent assay (ELISA)
since 1985 and was more recently confirmed for all patients with
Western blot testing.
Factor concentrates. Data related to CFC use had been recovered for each patient from archives of the two hemophilia centers
involved. More accurately, for the Barcelona cohort data were obtained from pharmacy records because the Pharmacy Service keeps
accurate records of CFC delivery to hemophilic patients. In Spain,
the treatment with CFC is covered bythe Public Health System
and its delivery is centralized in the Pharmacy Services of Public
Hospitals. For the Valencia cohort, data were obtained from patient
treatment diaries and clinical records. The amount of CFC used
yearly was divided by annual mean body weight to express CFC as
international units per kilogram per year. Finally, the arithmetical
T IS WELL ESTABLISHED that clotting factor concentrates (CFC), especially factor VI11 concentrates, widely
used in recent years in themanagement of hemophilia interact with immune function. This fact is supported by in vitro
data. Factor VI11 concentrates inhibit in vitro lymphocyte
proliferation and interleukin-2 production by T lymphocytes’.’ and downregulate monocyte f u n ~ t i o nThese
.~
observations have not been found with modem CFC, which are
largely more purified from plasma source than are classic
intermediate-purity concentrates (100 to 3,000 IU/mg of
plasma protein v 0.5 to 25 IU/mg). Therefore, it is suggested
that plasma proteins contaminating the intermediate-purity
concentrates, which are not present in the modem high-purity
preparations, are factors interacting with immune functions.
The nature of substances interfering with immune system
has not been established, although it is clear that they are
not major contaminating proteins (eg, fibrinogen, fibronectin,
Igs, and alb~rnin).~
Although notwell established, it has
been postulated that CFC act by increasing virus shedding
by human immunodeficiency virus (H1V)-infected T lymphocytes after alloantigen stimulation by CFC contaminants
and byan inhibitory effect on normal T-helper lymphocytes.4.’
The immunomodulating effect of CFC has caused great
concern with regard to progression of HIV infection in hemophiliacs. Although different studies following a variety of
designs have been focused on this subject,”’ the impact of
CFC on the outcome of HIV infection in hemophiliacs is
still controversial.”
In this study, a well-characterized cohort of HJY-infected
hemophilic patients from two centers of hemophilia were
followed-up retrospectively from 1983 to 1993. The goal of
this study was to estimate the effects of CFC use on the
incidence of acquired immunodeficiency syndrome (AIDS)defining events and mortality, after controlling for individual
age, severity of clotting factor deficiency, and other potential
risk factors.
MATERIALS ANDMETHODS
Study population. All HIV-l-infected patients routinely controlled at the beginning of 1983 in two hemophilia centres (Unidad
Blood, Vol 86, No 6 (September 15), 1995 pp 2213-2219
From the Hemophilia Centre, Research Unit, and Pharmacy Service, Hospital General Universitario Vall d’Hebron. Barcelona: and
the Congenital Bleeding-disorders Centre, Hospital La Fe, Valencia,
Spain.
Submined December 5, 1994; accepted May 16, 1995.
Address reprint requests to JosC B. Montoro, PhD, Unitat de
Hemofilia, Hospital Vall d’Hebron,Pg. Vall d’Hebron 119-129,
08035 Barcelona, Spain.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
0 1995 by The American Socieiy of Hematology.
ooW-4971/95/ssw-0026$3.00/0
2213
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221 4
MONTORO ET AL
Table 1. Characteristics of Each Cohort and the Two Cohotts as a
Whole at tho End of the Follow-Up (1993)
Total
Valencia
Barcelona
No. of patients
225
141
84
Coagulation disorder
Hemophilia A
197 (88)
119 (841
(93)
76
Hemophilia B
19 (81
(9)13
6 (7)
Other'
(6)
9
(4)
9
0
Severityt
(73)103(74)166
63 (751
Severe
Moderate (19) 16 (17) 24
40 (18)
Mild
19 (81 (10) 14
5 (61
Previous CFC use*
5700 IUkghlr
(63)
89
NA
89 (63)
>700 lU/kg/yr
52 (37)
52 (37)
NA
Age at entry (yr)
18 2 19
12
_f 12
16 2 12
Mean CFC use (IU/
993 2 1,207 965
2 1,2321,041
? 1,170
kg/yrl
Group
Death AIDSrelated
(32)
72(33)
47
25 (35)
AIDS
17 ( 2 0 )
49 (22)
32 (23)
CD4+ count of 200-
400
(34) 77
(351
P
,048
NS
.048
NS
2948 (34)
CD4+ count of
(161 2400
13 (10) 14 (12) 27
NS
Abbreviations: NS, not significant; NA, not available.
Includes von Willebrand's disease, factor l1 deficiency, and factor X deficiency.
t According to laboratory criteria: severe (plasma activity of deficient factor
<l% standard activity in healthy subjects), moderate (1% to 5%). and mild (>5%).
*Mean CFC use of years 1981-1982.
continuous variables was estimated with Pearson's correlation coefficient.
Confusion and interaction effects of age were evaluated by multiple logistic regression analysis. The criteria used to enter or remove
a variable from the model were a probability of the x' approximation
for the likelihood ratio of 0.05 and of 0.1, respectively, and aconvergence criteria of estimate parameters and logarithm of the likelihood
ratio of 0.0001.
The survival curve estimation and the proportion of patients free
from AIDS were assessed by means of the Kaplan-Meier productlimit estimator. The median time from entry and cumulative proportion of patients free from event were computed. Pairs of survival
curves were compared using the log-rank test. Factors affecting outcome were assessed with the Cox proportional-hazards regression
model. Statistical tests of the regression coefficients were based on
the x* approximation for the likelihood-ratio statistic. The criteria
used to enter or remove a variable were a probability of 0.05 and
of 0.1, respectively. The combined effects of the risk factors were
explored using a statistical test for interaction. Time was measured
by years, given that the follow-up period includes more than 10
divisions of this unit.
All reported P values are two-sided. A P value less than .05 was
considered to indicate statistical significance.
RESULTS
Study population. The characteristics of each cohort and
of the whole group are shown in Table 1. The two cohorts
were homogeneous in severity of the clotting factor defimean of yearly administered CFC was used to express CFC use as
ciency, mean CFC use, and finalstatus. Little difference was
a single datum for each patient. To avoid confusion, the amount
present
with respect to hemophilia type and age. The whole
of CFC administered since AIDS progression was not considered.
group was relatively young (median, 16 years; 25th to 75th
Although differences among factor concentrates were not considpercentiles range, 8 to 25 years). There was a predominance
ered, it should be stated that most of the CFC administered corresponds to the so-called intermediate-purity products; ie, 1983
of hemophilia A (88%) and of patients with severe (<l% of
through 1991, intermediate purity; 1992 through 1993, high purity.
the standardactivity) deficit of clotting factor (74%). Median
CFC use in patients who died between 1983 and 1985 was estimated
CFC use was 684 IU/kg/yr (25th to 75th percentiles range,
from data belonging to 1981 and 1982.
280 to 1,416 IU/kg/yr).
Previous CFC use was defined as mean CFC use before seroconThe Shapiro-Wilks testshoweda least departure from
version from data belonging to 1981 and 1982. It was only available
normality
for a square root of both age and CFC use. Therefor the Barcelona cohort.
fore,
all
statistical
tests were performed with the respective
Clinical events. Causes of death were obtained from clinical
square root.
records and death certificates (85%), autopsy reports (4%). and offiThe final status was AIDS-related death in 72 (32%) pacial declarations of AIDS-related death to Health Autorities (1 1 S).
tients, AIDS in 49 (22%),lymphocyte CD4' cell counts less
Any death occumng during the follow-up period was defined as
HIV related unless it was conclusively known not to be HIV related.
than 400 cells/mL in 77 (34%), and CD4' cell counts equal
Progression to AIDS was defined according to the Centers for
or more than 400 celldmL in 27 (12%).
Disease Control (CDC) criteria of 1993 for the1992-1993 period and
Progression to AIDS and mortality. Table 2 shows the
according to the CDC criteria of 1987 for the 1983-1991 p e r i ~ d . ~ ~ , clinical
'~
characteristics of patients that developed AIDS and
Statistical analysis. Statistical analysis was performed by using
of patients who died of AIDS compared with those that did
commercially available software (SPSS/PC+, version 4.0 [SPSS Inc,
not. No association was found between coagulation disorder
Chicago, IL] and BMDPIDYNAMIC, version 7.0 [BMDP Statistical
or seventy of the clotting factor deficiency and either AIDS
Software, Cork, Ireland]). The distribution of all quantitative varior death; however, a stronglystatistically significant associaables was examined to detect significant departures from normality
tion was found between progression to AIDS or death and
by means of a Shapiro-Wilks test. When present, a newly derived
variable with better performance was computed. However, for deage, mean CFC use, and previous CFC use. The mean age
scriptive purposes, the mean ? SD was used independently of the
was 21 2 14 years in patients who developed A I D S and 15
distribution.
t 9 years in those that did not (P = .001). The mean age
Intergroup comparisons involving quantitative variables were perwas 24 -C 15 years in patients who died and 15 ? 10 years
formed using two-tailed t-tests for independent samples. The nonparin those who are alive at the end
of the study (P .OOO5).
ametric Mann-Whimey test wasusedwhenthe
variable did not
The
mean
CFC
use
was
770
2 819 IUkg/yr versus 1,253
follow normal distribution. A x
' test, or a Fisher exact test when
1,503 IU/kg/yr (P = .002) on progression to AIDS and
appropriate, was used for categorical data. A Mantel-Haenszel test
559 t- 482 IU/kg/yr versus 1,198 t 1,381 IUkglyr (P <
for linear association was used for ordinal data. Relative risks and
.OOO5) on death. The relative risk of patients with previous
95% confidence limits were calculated. The association between
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Table 2. Characteristicsof Patients With AIDS or Death Among 225
Hemophilic Patients
P
AIOS
No. of patients
Mean CFC use
5700 IU/kg/yr
>700 lU/kg/yr
P
(32)
72
(54)
121
Coagulation disorder
62(53)
104
Hemophilia A (32)
Hemophilia B
(68) 13
Other*
4 (44)
NS
Severityt
Severe
92 (55)
Moderate
22 (55)
NS
Mild
7 (37)
Previous CFC use*
~ 7 0 IUlkgh/r
0
59 (66)
.0024
>700 IU/kg/yr
20 (40)
Age at entry
47 (44)
s15 yr
>l5 yr
Mortality
74
7 (37)
3 (33)
NS
52 (311
16 (40)
4 (21)
NS
42 (47)
5 (10)
<.0001
22
(21)
.0072
.0008
50
(63) (42)
73 (65)
.0017
48 (43)
49 (43)
23 (20)
.0004
Abbreviation: NS. not significant.
Includes: von Willebrand's disease, factorIIdeficiency, and factor
X deficiency.
t According to laboratory criteria: severe (plasma activity of deficient factor <l% standard activity inhealthy subjects), moderate(1%
to 5%), and mild (>5%).
Mean CFC use of years 1981-1982.It was only available from the
Barcelona cohort (141 patients).
*
CFC use higher than 700 UIflrglyr was 0.6 (confidence limits,
0.4 to 0.8) to develop AIDS and 0.2 (0.1 to 0.6) to die.
The association between the mean CFC use and death
(Fig 1) or AIDS (Fig 2) was not statistically significant in
several strata when subgroup analysis was performed according to coagulation disorder, severity of clotting factor
M m
deficiency, and previous CFC use. Nevertheless, these Variables were not considered to be confounders or modifiers
but to be intermediates and were therefore not included in
the logistic regression model. When stratified by age, both
significance and intensity of the association between mean
CFC use and AIDS or death strongly changed. Furthermore,
these two variables are inversely correlated (Pearson r =
-.306, P < .OOOS). Therefore, in subsequent analysis, the
effect of age on mean CFC use was controlled.
Multiple logistic regression retained both the squared root
of the mean CFC use and the squared root of the age as
independent predictors of death (global X', 34.30; P <
.oooO5) and progression to AIDS (global X', 15.81; P =
.OOO4) without interaction between these two risk factors.
These logistic functions explain the 72.9%and 64.4%of the
variability found, respectively.
The variation of odds on death was a decline of 0.96 (95%
confidence limits, 0.94 to 0.99) per unit of the square root
of the mean CFC use and an increase of 1.49 (1.19to 1.87)
per unit of the square root of the age. The variation of odds
on progression to AIDS was a decline of 0.98 (0.96to 1 .00)
per unit of the square root of the mean CFC use and an
increase of 1.26 (1.04to 1.53) per unit of the square root of
the age.
When these risk factors were evaluated as dichotomous
data (<700 IUkglyr v >700 IUkg/yr and 5 15 years v >15
years), risk odds ratios were 0.39 (confidence limits, 0.21 to
0.71) for more CFC use and 2.43 (1.32 to 4.49) for age
on death and 0.46 (0.27 to 0.80) and 1.87 (1.08 to 3.24),
respectively, on progression to AIDS. The adjusted relative
risks of higher consumers were 0.48 for younger patients
and 0.56 for older patients on death and 0.66 and 0.74 on
progression to AIDS, respectively.
The median survival time was more than 12 years for
death (75th quantile, 10 years) and 11 years for progression
(* SD)CFC ust by vital stahls
Dccrastd
(n=72)
Alive
(~153)
p
56U499 1233t13904.0005
624a3711293t1493
NSc
2 W 125 Wlt 377 NS
Fig 1. A d e t i o n between
mean CFC use anddeath. *NS
denotes not significant.
*Includes von Wilebrand's disease,
factor II ddciency, and factor X
dedkiency. 'According to Iaboratory criteria: severe (plasma activ-m of dofident factor 4 %
standard activity in healthyaubjectsl, moderate (1%to 5%). and
mild ( 1 5 % ) . 'Mean CH: use of
years 1981-1982.
595+ 502 143%1482
525+451 68U 741
21U 104 18-7
333* 235 67U924
1407i 649 177W1596
4.o005
NS
NS
0.062
NS
633* 543138Oi1390 UI.0005
52& 454 971*1345 0.013
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2216
MONTORO ET AL
Mean (*SD)CFC use by AIDS ststus
AIDS
(n=121)
Cohort
Barcelona
Valencia
Coagulation disorder
Hemophilia A
Hemophilia B
o
t
h
e
r
'
Non AIDS
(n1104)
p
72& 915 127&1499
853* 6001229i1528
0.007
NS'
787* 8121288i1520
8 W 9 5 6 153M689
151* 142 27&403
NS
NS
886a 885 1533*1646
4-413
811* 811
194*93
192 298
NS
NS
0.002
SeveriqJ
SCVm
Moderate
Mild
Previous CFC uses
5'OOIU/kg/year
>700 IUkg/year
442i549 -943
1565t1235 1842i1700
4.0005
I
NS
l
NS
W
l
'
I
Age at entry
,SlSyears
>l5 years
102Z=t1058
1387*1446
610+
575
10721577
l ,
0.077
0.106
I
i
1
j,
J
dm
-lom
O
ma
C K : - d m O
to AIDS. By 5 and 10 years after seroconversion, death had
occurred in 8.44% (confidence limits, 5% to 12%) and 25%
(19% to 31%), respectively, and the cumulative incidence
of AIDSwas11%(7%
to 15%)and40%(32%to
46%),
respectively.
Negative association between the mean CFC use on the
time to die or develop AIDS and positive association with
age remain present, according to the Cox regression model
(global x*,32.78; P < .00005 for death; and global X',
11.81; P = .W06 for progression to AIDS). No significant
interaction was found between age and mean CFC use. Relative hazards on death were 0.97 (95% confidence
limits, 0.96
to 0.99) for the square root of the mean CFC use and 1.39
(1.17 to 1.65) for the square root of the age. Relative hazards
on progression to AIDS were 0.99 (0.97 to 1.00) and 1 . l 8
( l .03 to 1.34), respectively.
The log-rank test, after adjustment for age, showed that
the relative hazards in the patients with CFC use less than
700 IU/kg/yr is 0.53 (confidence interval, 0.33 to 0.86; Fig
3) on death and 0.57 (0.39 to 0.84; Fig 4) on progression to
AIDS.
DISCUSSION
In recent years, attention has been focused on the interaction between administered CFC and the immune system of
hemophiliacs seropositive to HIV-1." At this moment, most
of HIV-infected hemophiliacs have been switched to treatment with high-purity CFC. This fact makes it difficult to
undertake along-term prospective follow-up on the influence
of classic intermediate-purity CFC onthe occurrence of
AIDS-defining diagnoses and mortality of HIV-infected hemophiliacs.
In this cohort study, mortality and progression to AIDS,
adjusted for known risk factors, are strongly associated with
administered CFC, but, strikingly, higher amounts of CFC
ram
am
Fig 2. Association between
mean CFC use and p r o g d o n
to AIDS (see Fig l ) .
usage are associated with a slowing down in the progression
of HIV-1 infection to AIDS and AIDS-related mortality. As
with all other epidemiologic studies, it is possible that the
observed association is due to confounding resulting from a
risk factor that is correlated with both CFC exposure and
progression to AIDS or mortality. Potential confounders of
effects of CFC use not controlled in the study are unknown
at this moment. Nevertheless, it is important to state that
the results are consistent inboth cohorts (Barcelonaand
Valencia). Although the Valencia
cohort was notstatistically
significant, the magnitude of the effect is comparable. The
lack of significance in this case is probably related to the
relatively low number of patients of the Valencia cohort.
Assuming that CFC exerts a protective effect on HIV-1infected hemophiliacs, one would expect a longer survival
time in series involving hemophiliacs. In this cohort, there
is a mortality of 32% and a cumulative incidence of AIDS
of 54% after 11 years of follow-up. Studies in hemophiliacs
with similar follow-up periods are coincident and show mortality of 3 1% (12 years) and41 % (1 1 years) and cumulative
incidence of AIDS of66%and 42%(not 1993 CDC criteria),
respectively.l5.l6Unfortunately, differences, if present, with
other risk populations (transfusion recipients, homosexuals,
and injection-drug users)cannot be evaluated from a statistic
point of view. Nevertheless, the incidence of AIDS-related
malignancies, such as Kaposi sarcoma, are rare among hemophilic patients. Because this tends to occur in patients
with higher CD4+ cell counts than in patients with other
AIDS-defining conditions, it might be expected that people
with hemophilia would progress more slowly thanwould
other risk groups.I6
In light of the results it seems evident that there is no
association between coagulation disorder or seventy of hemophilia with progression of HIV
infection. These results
are coincident with those from a previous study.I7
The strong
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2217
FACTOR THERAPY AND HIV PROGRESSION IN HEMOPHILIA
I
L
100
90
80
70
60
50
40
1984
1982
1988
1988
1992
1990
Year
100
E
90
B
80
-.S
.-
's
70
n
m
n
e
60
S
m
n
Fig 3. Probability of survival among 107 patients
less or equal than 15 years (A) and 118 more than
15 years (B). Thick lines denote 65 (A) and 47 (B)
patients with higher CH: use b 7 0 0 IUlkglyr) and
thinner linm denote 42 (A) and 71 (B) patients with
lower CFC use ( ~ 7 0 lU/kg/yr).
0
50
I
1982
association between age and progression to A m S or mortality is not surprising given that it has been widely described
not only for hemophiliacs but also for other risk groups.'*
Patients with lower previous CFC use have a significantly
increased risk of progression to AIDS or death. Initially, it
was suggested that patients with smaller infecting inoculum
would probably have a slower progre~sion.'~,'~
This consideration might be true, but in our casethe strong association
between previous CFC and CFC use after starting the followup probably completely obscures such a supposition.
The strength of the observed association between CFC
use and AIDS-related mortality and progression to AIDS has
not been observed in previous studies. In most cases, CFC
use was not considered as a potential cofactor.I6The cumulative dose of plasma concentrate was not demonstrably related
to the incidence of AIDS even if stratified by age, as expressed by investigators in a previous study.17 However, it
must be stated that the crude cumulative dose of plasma
concentrate may not be the most accurate expression of CFC
use, as shown in an early evaluation of the Valencia cohort."
It is more realistic to normalize CFC use by weight and year,
excluding its use after progression to AIDS, thus avoiding
the influence of AIDS condition on CFC use. Nevertheless,
I
l
1884
1990 1988 1986
I
l
1992
Year
the latest studies show increasing coincidences with our results, ie, a faster progression towards AIDS in hemophiliacs
using lower yearly amounts of factor VI11 concentrates
(520,000IU) than those using higher amounts;' and that
78% of the current asymptomatic patients were severe hemophiliacs, receiving more than 20,000 Wyr.2'
This study provides precise estimates of the protective
effect of CFC on the progression of HIV infection in hemophiliacs. The relative hazard, adjusted for age, of AIDSrelated death in patients with higher CFC use (>700 IU/
kg/yr) is 0.53 (95% confidence interval, 0.33 to 0.86). For
progression to AIDS, the relative hazard is 0.57 (0.39 to
0.84). After 11 years of follow-up, death resulted in 20%
patients with a CFC use greater than the median (700 IU/
kg/yr) and in 43% patients of the lowest half of CFC use.
Progression to AIDS resulted in 43%and 65% patients, respectively.
Assuming that our results are not a consequence of another
unmeasured risk factods), an easy explanation for primary
protective mechanism cannot be given. Nonetheless, a hypothesis can be advanced. It is widely recognized that CFC,
especially classic intermediate-purity products, interact with
the immune system. The nature of this interaction is not well
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2218
MONTORO ET AL
*i
40
I
l982
I
1
1984
S
lE
8
l990
I
l988
Year
I
1Q%?
4
fig 4. ProbabSrtyof AIDS-fme among younger(A)
and older (6)pntbntu. Thdc lines donote patients
with higher CH: use and thinner linea denote patients with lower CFC use.
established, butthe ultimate consequence could be a delayed cyte IL-2 receptor expression by factor VIII concentrate: A possible
cause of immunosuppression in haemophiliacs. Br J Haematol
progression of HIV infection. Recently, increasing impor75:278, 1990
tance has been given to the presence of immunomodulating
3. Eibl MM, Ahmad R, Wolf VM, Linnau Y,Gotz E, Mannhalter
proteins in intravenous Igs, another
group of plasma-derived
J W : A component of factor VIII preparations which can be separated
dr~gs.".~Similarly, CFC (with the exception of very high
from factor VI11 activity down modulates human monocyte function.
punty preparations) contain appreciable amounts of transBlood 69: 1153, 1987
forming growth factor-p (TGF-p).25
4. de Biasi R, Rocino A, Miraglia E, Mastrullo L, Quirino AA:
Finally, it is quite important to more deeply evaluate (in
The impact ofavery high purity factor VI11 concentrate on the
immune system of human immunodeficiency virus-infected hemoother series) the association between CFC use and the prophiliacs: A randomized, prospective, two-year comparison with an
gression of HIV infection in hemophilic patients to assess
intermediate purity concentrate. Blood 78:1919, 1991
accurately, if confirmed, the power of the effect andto iden5. Seremetis SV, Aledort LM, Bergman GE, Bona R, Bray G,
tify and isolate the responsible substances.
ACKNOWLEDGMENT
We are indebted to Dr Andr6s L6pez for his expert assistance in
statistical computer programming.
REFERENCES
1. Thorpe R, Dilger P, Dawson NJ, Bmwcliffe TW: Inhibition of
interleukin-2 seaetion by factor WI concenttates: A possible cause of
immunodepressionin haemophiliacs. Br J Haematol 71:387, 1989
2. Hay CRM, McEvoy P,Duggan-Keen M: Inhibition of lympho-
Brettler D, Eyster ME, Kessler C, Lau TS, Lusher J, Rickles F:
Three-year randomized study of high-punty or intermediate-purity
factor VI11 concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status. Lancet 342:700, 1993
6. Hilgartner MW, Buckley JD, Operskalski EA, Pike MC, Mosley J W : Purity of factor VIII concentrates and serial CD4 counts.
Lancet 341:1373, 1993
7. Mannucci PM, Gringeri A, de Biasi R, Baudo F, Morlini M,
Ciavarella N Immune status of asymptomatic HIV-infected hemophiliacs: Randomized, prospective, two-year comparison of treatment with a high-purity or an intermediate-purity factor VIII (FVIII).
Thromb Haemost 67:310, 1992
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
FACTORTHERAPY AND HIV PROGRESSION IN HEMOPHILIA
8. Goedert JJ, Cohen AR, Kessler CM, Eichinger S , Seremetis
S, Rabkin CS, Yellin FJ, Rosenberg PS, Aledort LM.
Risk of immunodeficiency, A I D S , and death related to purity of factor VIII concentrate. Lancet 344:791, 1994
9. Gjerset GF, PikeMC,Mosley J W , Hassea J, Fletcher MA,
Donegan E, ParkerJ W , Counts RB, Zhou Y, Kasper CK,
Operskalski
EA: Effect of low-and intermediate-purity clottingfactor therapy on
progression of human immunodeficiency virus infection in congenital clotting disorders. Blood 84:1666, 1994
10. Berntorp E Impact of replacement therapy on the evolution
of HIV infection in hemophiliacs. Thromb Haemost 71:678, 1994
11. Kroner B, Rosenberg PS, Aledort LM, Alvord WG, Goedert
JJ: HIV-1infection incidence among personswithhemophiliain
United States and Western Europe, 1978-1990.J AIDS 7:279, 1994
12. Chiarotti F, Palombi M, Schinaia N, Ghirardini A, Bellocco
R Median time from seroconversion to AIDSin italian HIV-positive
hemophiliacs: Different parametric estimates.
Stat Med 13:163,1994
13. Centers for Disease Control: Revision of the CDC surveillance case definition for acquiredimmunodeficiencysyndrome.
MMWR CDC Surveill S u m 36:1, 1987
14. Centers for Disease Control: 1993 Revised classificationsystem for HIV infection and expanded surveillance case definition for
AIDS among adolescents and adults. MMWR CDC Surveill Summ
41(RR-17):1,1992
15. Sabin C, Phillips A, Elford J, Griffiths P, Janossay G,Lee C:
The progression of HIV disease in an haemophilic cohort followed
for 12 years. Br J Haematol 83:330, 1993
16. Lee CA, PhillipsAN, Elford J, Janossy G,GriffithsP, Kernoff
P: Progression of HIV disease in an haemophilic cohort followed
for 11 years and the effect of treatment. Br Med J 303:1093, 1991
17. Goedert JJ, Kessler CM, Aledort LM, BiggarRI, Andes WA,
White G C , Drummond JE, Vayda K, Mann DL, Eyster ME, Ragni
MV, Lederman MM, Cohen AR, Bray GL, Rosenberg
PS, Friedman
2219
RM, Hilgartner MW, Blamer WA, Kroner B, Gail MH: A prospective study of human immunodeficiency virus type I indection and
the development of AIDS in subjects with hemophilia. N Engl J
Med 321:1141, 1989
18. Selwyn PA, Alcabes P, Hartel D, Buono D, Schoenbaum EE,
Klein RS, Davenny K, Friedland GH: Clinical manifestations and
predictors of disease progression in drug users with human immunodeficiency virus infection. N Engl J Med 327:1697, 1992
19. Ward J W , Bush TJ, Perkins HA, Lieb LE, Allen JR, Goldfinger D, Samson SM, Pepkowitz SH, Fernando LP, Holland PV,
Keinman SH, Grindon A J , Gamer JL, Rutherford GW, Holmberg
SD: The natural history of transfusion-associated infection with human immunodeficiency virus. N Engl J Med 321:947, 1989
20. Lorenzo JI, Molina R,Senent ML, Mom6 E, Lerma MA,Dasi
MA, Monteagudo E, Aznar JA: Progressi6n a SIDA en hemofilicos
seropositivos frente al VM. Sangre 37:169, 1992
21. Schinaia N, Ghirardini AMG, Mazzucconi MG, Tagariello
G, MorliniM, Chimtti F, and the GICC:Clinical factors associated
with progressionto AIDS in the italian cohort
of HIV-positive hemophiliacs. Thromb Haemost 72:33, 1994
22. Stieltjes N, Sultan Y, Rothschild C, Torchet MF, Laurian Y,
NavarroR,FressinaudE,Parquet-GernezA,Fonlupt
J, Berthier
AM, and the French Hemophilia Study Group: Long-term survival
of HIV-infected patients with haemophilia. Haemophilia 1:33, 1995
23. Blascyk R, Westhoff U, Grosse-Wilde H: Soluble C M , CD8
and HLA molecules in commercial immunoglobulin preparations.
Lancet 341:789, 1993
JM, Hodge T W , Hooper
24.LamL,WhitsettCF,McNicholl
J: Immunologically active proteins in intravenous immunoglobulin.
Lancet 342:678, 1993
25. Wadhwa M, Dilger P, Tubbs J, Mire-Sluis A, Barrowcliffe
T, Thorpe R Identification of transforming growth factor$ as a
contaminant infactor VI11 concentrates: A possible link with immunosuppressive effects in hemophiliacs. Blood 842021, 1994
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1995 86: 2213-2219
An association between clotting factor concentrates use and
mortality in human immunodeficiency virus-infected hemophilic
patients
JB Montoro, J Oliveras, JI Lorenzo, JM Tusell, C Altisent, R Molina and AI Ayestaran
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