Hritisli /ourr~a/of Haenrutologlj, 1992.

81, 109-1 12

Incidence of AIDS in HIV-1 infected thalassaemia patients

D O M I N I O UG.E COSTAGLIOLA.' ROBERTGIROT,' P A O L O REBULLA' A N D J E A N - J A C Q U ELEFRhRE4

S
on behalf of the European and Mediterranean W.H.O. Working Group on Haemoglobinopathies and Cooleycare
'ZNSERM U2h 3 et SC4, Universite Paris 7, Paris, France, 'Laboratoire d'Hematologie,
Hdpital Necker-Enfants malades. Paris. France, 'Centro Trasfusionale e di Immunologia dei Trapianti,
Ospedale Maggiore. Milano. Ztuly. and 'Znstitut National de Transfusion Sanguine, Paris, France

Received 8 August 199 1; accepted for publication 12 December 1 9 91

Summary. To estimate the cumulative incidence of acquired
immunodeficiency syndrome (AIDS) in thalassaemia major
patients (TMP) human immunodeficiency virus (HIV-1)
infected through transfusion. 79 seropositive TMP were
studied. At inclusion. mean age was 12.4f6.6 years; 40
were men: 2 1 were splenectomized. Centers for Disease
Control, 1986 (CDC) stages and prescription of zidovudine
were noted at least once a year. Cumulative incidence of AIDS
and standard error were calculated using non parametric life
table method. Age, sex. acute infection and splenectomy
associations with progression to AIDS were tested using
Breslow statistic. The median follow-up period was 4 years
11 months. At the end of the study period, 4 3 TMP were in
CDC stage 11. 2 3 in CDC stage 111 and 13 in CDC stage IV,
including seven AIDS cases, of whom three had died. Four
subjects died of other causes. Only two patients were treated
with AZT prior to the occurrence of AIDS. Rate of progression
to AIDS was not associated with acute infection, splenec-
tomy, age, or sex. A cumulative AIDS incidence rate of 1.4%
(SE 1.3%) was observed at 3 years and of 9% (SE 4%) at
5 years.

The natural history of human immunodeficiency virus (HIV)
infection in patients infected through transfusion has primar-
ily been studied in haemophiliacs (Darby et nl. 1989: Goedert
et ul, 1989; Schinaia et d.199 1 ) and in cohorts of patients
transfused with different blood products and suffering from
different pathologies of variable prognosis (Ward et ul, 1989).
We previously reported (Boiteux Pt RI. 1985: Lefrere & Girot.
1989) the frequency of HIV infection in thalassaemia major
patients (TMP).who were regularly transfused with packed
red cells (on average 30 units per year and increased with
age) as well as the date of introduction of systematic blood
donation screening for HIV antibodies in different countries
(Lefrere 6; Girot. 1987). The follow-up of such individuals
appears of interest in order to describe the natural history of
transfusional HIV infection. due to the particularities of
seropositive TMP (STMP) in comparison with other patients
infected through transfusion. Indeed, STMP were infected
through regular transfusions of packed red cells. while
haemophiliacs were infected through transfusion of anti-
haemophiliac concentrates. In addition, because TMP differ
from haemophiliacs in their immunological status, the
consequences of HIV infection may differ in these two
populations. STMP also differ from other HIV-infected non-
Correspondence: Dr Robert Girot. Laboratoired'Hematologie. HBpi-
tal Necker-Enfants Malades. 149 rue de Sevres. 75743 Paris Cedex
1 5 , France.
haemophiliac transfused patients. Previously published
cohorts of non-haemophiliac patients HIV-infected through
transfusion included patients of very variable age. having
received different blood products, and having an important
rate of mortality (due to the disease which necessitated
transfusion) within 1 year after transfusion (Ward et al,
1989). The young age of STMP generally allows an exclusion
of risk factors for HIV infection other than transfusion. In
addition, TMP as well as haemophiliac patients are regularly
followed up by their physician and the rate ofdropout is likely
to be lower than with other groups of HIV-1 positive patients,
including other patients infected through transfusion.
The aim of this study was to evaluate the risk of progression
to clinical manifestations of acquired immunodeficiency
syndrome (AIDS) in a cohort of HIV-infected TMP and to
correlate the outcome with sex. age at inclusion, existence of
an episode of acute infection when documented, and splenec-
tomy.
PATIENTS AND METHODS
Patients
79 HIV- 1 seropositive (positive Elisa. with confirmation by
Western blot, showing a typical pattern of HIV infection)
TMP were included in the study from centres participating in
the European and Mediterranean W.H.O. Working Group on
Haemoglobinopathies and/or in the Cooleycare programme

109
110 Dominique G. Costagliola et al
(Kebulla et al. 1991). They were regularly followed up in 32
centres (in Brazil. Cyprus, France, Greece, Italy, United
Kingdom and Spain) for regular transfusions of packed red
cell units. The majority of the patients included were followed
in Italy (71%)and Greece (16%)just as in the Cooleycare
programme. The diagnosis of thalassaemia major was done
through family study, blood counts and haemoglobin electro-
phoresis. For each patient included, the follow-up period
ranged from the time when first diagnosed HIV-I seropositive
until June 1989. CDC stage (Centers for Disease Control,
1986), prescription of zidovudine and dead/alive status were
noted at least once a year. An episode of acute HIV infection
(stage I of CDC classification) was obtained from medical
records.
At inclusion, mean age was 1 2 . 4 f 6 . 6 years: 40 were
male: 2 1 were splenectomized. None had any risk factors of
HIV infection other than transfusion.
Methods
Estimation ofthe date of seroconversion.The HIV seroconver-
sion interval was defined as the period between the last
negative test and the first positive test. When no negative test
was available, the date of the last negative test was defined as
either 1 January 1980 or the date of birth for patients born
after 1 January 1980. The procedure described by Darby et al
( 1 990) was applied. It was assumed that the probability of
seroconversion was piecewise constant in each of the periods
1 January 1980 to 1 January 1983. 1 January 1983 to 1
January 1986. and 1 January 1986 to 30 June 1989. This
model was selected on the basis of the two-stage parametric
regression model of Brookmeyer & Goedert (1 989). Several
models for the probability of seroconversion were tried
% ENTERING STAGE IV
OR DEVELOPING AIDS
O i I - - -
0 0.5 1 1.5
YEARS AFTER SEROCONVERSION
Number at risk
Stage IV 79 79 79 79
AIDS 79 79 79 79
Pig 1. Estimated percentage of patients entering stage IV of the CDC classification or developing AIDS by time since estimated date of
seroconversion and number of patients at risk (that is the number of patients still exposed to the risk of entering stage IV-or to the risk of
developing AIDS-at a given time).
including exponential, linear and piecewise constant with
various jump points. The latter was found to be the best
model, that is, corresponding to the greater likelihood value.
Using that model, the probabilities of seroconversion were
estimated from the data according to the method suggested
by Brookmeyer & Goedert (1989). In accordance with the
method used by Schinaia et a1 (1991).it was assumed for the
remainder of the analysis that seroconversion for each
patient took place on the date expected from the estimated
distribution of seroconversion conditional on its lying
between the dates of the last seronegative and the first
seropositive tests.
Statistical analysis. Cumulative incidence of AIDS (and of
stage IV of CDC classification) and standard error were
calculated using the non-parametric life table method.
Associations of symptomless period with sex, age (below or
above 12 years of age), acute infection and splenectomy were
tested using Breslow statistic. The cutoff point of age was
chosen at the observed median age and, as in other studies,
age was not taken as a continuous variable (Darby et al,
1989: Downs et al, 1991: Goedert et al, 1989). Analysis was
carried out using BMDP Statistical Software (IL).
KESULTS
Date of HIV infection was known in 16 TMP due to a negative
serology preceding the first positive test. An acute HIV
infection was noticed in 1 1 subjects.
The median follow-up time after the estimated date of
seroconversion until the diagnosis of AIDS, death or 30 June
1989 was 4 years 11 months: only 10%of the subjects were
followed up for more than 5 years and 4 months.
I I
2 2.5 3 3.5 4 4.5 5
78 75 71 70 61 55 38
78 75 72 71 64 58 38
 AZDS in HZV-I Infected Thalassaemia Patients 111
Table 1. Association between studied factors and progression to stage IV of the CDC
classification and to AIDS

Progression to stage IV Progression to AIDS

No. progression/ No. progression/

no. subjects P value' no. subjects P value'

Sex Men 6/40 0.325 3/40 0.354

Women 7/39 4/39
Age (years) < 12 7/43 0.774 414 3 0.523
> 12 6/36 3/36
Acutc infection No 9/59 0.825 5/59 0.368
Yes 2/11 1/11

Splenectomy No 9/58 0.72 1 4/48 0.718

Yes 412 1 312 1

' Breslow statistic.

Table 11. Comparison with previously published results in similar age group

Estimated percentage developing

AIDS (approximate
Age at first 95% confidence interval)
positive test
Kcfercnce Transmission group No. (yr) At 3 years At 5 years
-~

Higgar ('I 01 (1990) Haemophiliac patients 107 < 18 2.1 (0.0-5.6) 5 (0-1 1)
I>drby PI nl ( 198 9 ) Haemophiliac patients 579 < 25 l(O.4-2) 4 (3-6)
(hedert rt nl ( 19x9) Haemophiliac patients 12 5 < 18 0.8 (0'0-2.4) 4.4 (0.7-8.1)
l'rcscnt study Thalassaemic patients 79 < 25 1.4 (0-4) 9 (2-17)

By 3 0 June 1984. of the 7 9 patients included in the study.
4 3 patients were in CDC stage 11, 2 3 in CDC stage 111. and 1 3
in CDC stage IV. including seven diagnosed as having AIDS.
When all patients were considered together. none had
developed AIDS within the first 2 years. Three years after
seroconversion 1 '4% had developed AIDS and 4.4%were in
stage IV (Fig 1 ), Five years after seroconversion. 9% had
developed AIDS and 16.6%were in stage IV.
The rate of progression to AIDS (and to stage IV) was not
significantly associated with sex, age, acute infection and
splenectomy (Table I). Only two subjects were treated by
zidovudine prior to the occurrence of AIDS.
Three subjects had died of AIDS and four from causes other
than AIDS (haemochromatosis).
DISCUSSION
This population provided us with the opportunity to study the
natural history of HJV infection in young patients contami-
nated only through packed red cell transfusion, without
other risk factors of HIV infection and with a low mortality
rate as compared to other transfused patients. As in other
populations. the HIV-1 infected subjects were progressing
towards the disease and a cumulative AIDS incidence rate of
9 4% was observed a t 5 years. AIDS now appears as a new
cause of death in thalassaemia major patients along with
haemochromatosis. heart disease, liver diseases. and other
infections (Zurlo et nl, 1 9 8 9 ) .
As with any cohort, there are several potential biases in the
estimation of the cumulative incidence of AIDS and of AIDS
related complex (ARC) or AIDS. On the one hand, it is possible
that some of the patients included in this study were tested
because they presented signs of the HIV infection: this
phenomenon can inflate the percentage of those progressing
to clinical manifestations of the disease. On the other hand,
some AIDS cases could have been missed, which would lead
to an underestimation of those progressing towards the
disease. It seems unlikely that antiviral therapy and various
prophylaxis played a major role within the context of this
survey. due to the small number of treated subjects during the
study period. A major source of uncertainty remains due to
the fact that the exact date of contamination is unknown.
Therefore, a statistical procedure was necessary to estimate
the progression to AIDS in an unbiased manner (Brookmeyer
& Gail. 1 9 8 7 ) .
No relationship was found between the rate of progression
112 Dominique G. Costagliola et al
to AIDS and the fact that the patient was splenectomized prior
to the infection. This finding contradicts that of Landonio et al
(1988). but it is possible that the size of our sample was not
large enough to detect a n effect. So far, the results on
progression to AIDS have been established mostly in men
(whether homosexual or haemophiliac): in our study, no
relationship was found between sex and the progression to
AIDS. With regard to acute infection, no difference was
noticed in the rate of progression to AIDS in those who had
had a n acute infection; however, when interpreting this
result, it should be kept in mind that the data concerning the
existence of a n acute episode were obtained retrospectively.
In our group, which only included patients under 2 5 years of
age. n o relationship between age and progression to AIDS
was observed. This may be due to the homogeneous age
range of our group of subjects. In children under the age of 5,
Contaminated through transfusion, the rate of progression to
AIDS was estimated to be higher than in older subjects
(Downs e l al, 1 9 9 1), No such tendency was observed in our
group in which only six subjects where under the age of 5 at
inclusion. When looking a t other estimates of progression to
AIDS in similar age groups. the estimates found were
primarily for subjects infected by the same route, namely
haemophiliac children (Table 11). The present findings were in
the same range at 3 years and a t 5 years although in our
study there is a non-significant higher rate of progression to
AIDS at 5 years. As in young haemophiliac patients, the rate
of progression to AIDS in this age group seems lower than
that reported in older age groups: patients receiving trans-
fusions (Costagliola et al, 1989: Downs et al, 1991 : Ward et al.
1989), older haemophiliac patients (Biggar et al. 1990:
Darby et al, 1989: Goedert et al, 1989: Lee ct al. 1989:
Schinaia et al. 1991) and homosexual men (Biggar et al.
1990; Munoz et ul. 1989). This difference, however, is not
always significant (Rutherford et al. 1990). Age appears to be
a more important factor than the kind of contaminated blood
products in explaining the rates of progression to AIDS in
patients contaminated through blood transfusion.
A C K N 0W LE DG M ENT S
This work was supported by ANRS grants no. 9 0 0 5 8 (K.
Girot) and 90182 (D. Costagliola).
This paper is a report from the European and Mediterra-
nean W.H.O. Working Group on Haemoglobinopathies and
Cooleycare: Doctors providing data: Drs Aguado. Angastinio-
tis, Avanzini. Barrelia. Batzella. Bellavita, Bellomo, Bozkurt.
Carnelli. Carta. Corvaglia. Cuccuru. Dessi, Di Gregorio, Di
Venere. Farzati. Forni. Gaudiano. Girot, Karagiorga-Lagana,
Lena-Russo, Malfitano. Meo. Modell. Monguzzi, Montuori.
Mulas. Politis. Rizzone, Schettini, Tricta. Vania. Wonke.
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