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Hritisli /ourr~a/of Haenrutologlj, 1992.

81, 109-1 12

Incidence of AIDS in HIV-1 infected thalassaemia patients

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

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


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

On the one hand. Three subjects had died of AIDS and four from causes other some AIDS cases could have been missed. 9% had estimation of the cumulative incidence of AIDS and of AIDS developed AIDS and 16.4 (0-4) 9 (2-17) By 3 0 June 1984.8 (0'0-2.368 Yes 2/11 1/11 Splenectomy No 9/58 0.825 5/59 0. subjects P value' no. including seven diagnosed as having AIDS. Association between studied factors and progression to stage IV of the CDC classification and to AIDS Progression to stage IV Progression to AIDS No.1 (0. Only two subjects were treated by phenomenon can inflate the percentage of those progressing zidovudine prior to the occurrence of AIDS. acute infection and because they presented signs of the HIV infection: this splenectomy (Table I). heart disease.6) 5 (0-1 1) I>drby PI nl ( 198 9 ) Haemophiliac patients 579 < 25 l(O. seroconversion 1 '4% had developed AIDS and 4. and 1 3 9 4% was observed a t 5 years. due to the small number of treated subjects during the This population provided us with the opportunity to study the study period. a statistical procedure was necessary to estimate other risk factors of HIV infection and with a low mortality the progression to AIDS in an unbiased manner (Brookmeyer rate as compared to other transfused patients. the fact that the exact date of contamination is unknown. towards the disease and a cumulative AIDS incidence rate of 4 3 patients were in CDC stage 11.0-5.6%were in stage IV. it is possible The rate of progression to AIDS (and to stage IV) was not that some of the patients included in this study were tested significantly associated with sex.4%were in As with any cohort. cause of death in thalassaemia major patients along with When all patients were considered together. On the other hand. Three years after infections (Zurlo et nl.325 3/40 0. 1 9 8 7 ) .718 Yes 412 1 312 1 ' Breslow statistic. which would lead than AIDS (haemochromatosis).4) 4. and other developed AIDS within the first 2 years. Table 11.523 > 12 6/36 3/36 Acutc infection No 9/59 0. As in other & Gail. progression/ No.72 1 4/48 0.354 Women 7/39 4/39 Age (years) < 12 7/43 0. related complex (ARC) or AIDS. (yr) At 3 years At 5 years -~ Higgar ('I 01 (1990) Haemophiliac patients 107 < 18 2. to clinical manifestations of the disease. AIDS now appears as a new in CDC stage IV. liver diseases. nated only through packed red cell transfusion. to an underestimation of those progressing towards the disease.1) l'rcscnt study Thalassaemic patients 79 < 25 1. of the 7 9 patients included in the study. subjects P value' Sex Men 6/40 0. 2 3 in CDC stage 111. populations. 1 9 8 9 ) . Five years after seroconversion.4 (0. the HIV-1 infected subjects were progressing No relationship was found between the rate of progression . A major source of uncertainty remains due to natural history of HJV infection in young patients contami. progression/ no. 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. none had haemochromatosis. AZDS in HZV-I Infected Thalassaemia Patients 111 Table 1. age.7-8. It seems unlikely that antiviral therapy and various prophylaxis played a major role within the context of this DISCUSSION survey.4-2) 4 (3-6) (hedert rt nl ( 19x9) Haemophiliac patients 12 5 < 18 0.774 414 3 0. there are several potential biases in the stage IV (Fig 1 ). without Therefore.

G. As in young haemophiliac patients. 768-769. T..R. L. Rutherford. & Brunet.. Barrelia. Bellavita. Costagliola). Monguzzi. J. R. AIDS in similar age groups. & Girot. Philips. C. ciency syndrome (AIDS)-freetime after human immunodeficiency Girot) and 90182 (D. AIDS. S. 530-539. N. however. Ward.-M.. Mannuci.. Nature. R. A. Rizzone. & Valleron. A. 43..J.B. journal of Acquired Itnmunodejciency Syndrome. E.W. n o relationship between age and progression to AIDS Darby.. Politis. products in explaining the rates of progression to AIDS in Lefrere. range of our group of subjects. C. A. Lancet.O. 1 1 83-1 188. 1989). Gringeri.. Lancet. 73. & Gail.M. W. ( 1989) Incubation time for AIDS from French transfusion- In our group. Lifson.H. Corvaglia. result. but it is possible that the size of our sample was not blood transfusion. for the Cooleycare programme (1991) nean W.J.. and the InternationalRegistry of Seroconverters( 1 990) virus.. eta/ (1989)Survival exposure groups. 1064-1 068. 1. Rizza.. on behalf of the European and Mediterranean always significant (Rutherford et al. Age appears to be W. Darby. large enough to detect a n effect. 1989: human immunodeficiency virus infection in a haemophilic cohort.M. 4. Vania..G.J. In children under the age of 5. 321.H. A.. ( 1 99 1 ) Transfusion-associatedAIDS cases in Europe: Estima- primarily for subjects infected by the same route. and causes of death in thalassaemia major. A.J.Y.. Costagliola.M. British Medical journal. 6 8 1 4 x 9 . 1991 : Ward et al. Chiarotti.. R. Spooner. Forni. 805-8 1 3 . 45.R. American journal of Epidemiology. 385-391. DeStefano. Meo. 130. inclusion. C. J. 301. Modell. B.1. H.. 334-339. J. 338.. Bozkurt. journal of Hematology. 739-749. This may be due to the homogeneous age from infection with HIV to onset of AIDS in patients with haemophilia in the UK.A.Thakrar..C. Montuori.C. No such tendency was observed in our report on behalf of the directors of haemophilia centres in the group in which only six subjects where under the age of 5 at United Kingdom. 947-952. no difference was Centers for Disease Control ( 1986) Classification system for human noticed in the rate of progression to AIDS in those who had T-lymphotropic virus type Ill/lymphadenopathy-associatedvirus had a n acute infection. A. Wonke. Elford. The present findings were in cases. and the Italian Group ( 199 1 ) Progression to AIDS among Italian HIV-seropositive haemophiliacs. 1141-1 148. N. Carta. Lancet.. ii. Bellomo. the rate development of AIDS in subjects with hemophilia. Bass. no an application to hemophilia-associated AIDS. et a1 (1989)A prospective study there is a non-significant higher rate of progression to study of human immunodeficiency virus type I infection and the AIDS at 5 years. Cuccuru. D. namely tion of the incubation period distribution and prediction of future haemophiliac children (Table 11). Girot. Mulas.. Tricta. & Modell. F. 1990). rt al(1989)Acquired immunodefi- This work was supported by ANRS grants no.Perkins.P. Malfitano. Schinaia et al. 69. Batzella. 9. Costagliola et al to AIDS and the fact that the patient was splenectomized prior Boiteux. AIDS. 1990: Lee... Schettini. Biomctrrcs. & Girot. 298. Lena-Russo. This difference. tis. older haemophiliac patients (Biggar et al. (1987) Bias in prevalent cohorts. British fusions (Costagliola et al. which only included patients under 2 5 years of associated cases. J. Munoz et ul. Farzati. year follow up study. 5. e t a / (1988)Splenectomy that reported in older age groups: patients receiving trans- for severe HIV-related thrombocytopeniain heroin abusers.. & Contaminated through transfusion. British Medical journal. Avanzini. mia major.D. Brouard. New England jourrial of Medicine.J. 4. B. P. With regard to acute infection. So far. & Goedert. New England journal oJMedicine.A.R.. 1..* Kessler.. Doll. when interpreting this infections.. Hessol. M. R. F.H. R. Working Group on Haemoglobinopathies and Transfusion requirements and effects in patients with thalassae- Cooleycare: Doctors providing data: Drs Aguado. Working Group on Haemoglobinopathies (1989) Risk of HIV infection in polytransfused thalassaemia patients.. Gaudiano. A. Karagiorga-Lagana. et al (1990)Course of Carnelli. 1. 1989). AIDS incubation in 1891 HIV seroconverters from different Zurlo.O. R. of progression to AIDS in this age group seems lower than Landonio. Ghirardini. Lancet. R.. R. Girot. Rigaut. Schinaia.112 Dominique G. it should be kept in mind that the data concerning the ('ostagliola. 1059-1 066. is not Lefrere. 686. 1989: Goedert et al.&Cox. A C K N 0W LE DG M ENT S Mufioz. (1989) Incidence of AIDS and excess of mortality AIDS was estimated to be higher than in older subjects associated with HIV in haemophiliacs in the IJnited Kingdom: (Downs e l al. Nosari. 1991) and homosexual men (Biggar et al. Rizza. A. 1 9 9 1). Vilmer.1. virus type 1 (HIV-1)seroconversionin homosexual men.J. 3 12. progression to AIDS have been established mostly in men Brookmeyer. (1990)Time was observed. Bush. Laporte. (20). Di Gregorio.M.P. however. P.... Doll... C.A.. et al(1989)The natural history of KEFERENCES transfusion-associated infection with human immunodeticiency Higgar.D.H. When looking a t other estimates of progression to Downs. 290-29 1 .A. . G.-J. et al (1985) Lymphadenopathy to the infection...M. M. Wang.-C. 1990. relationship was found between sex and the progression to 325-335. P.648-649.. ii. British journal of Haematology.. N. 228-234. Di HIV-I infection in a cohort of homosexualand bisexual men: an 1 1 Venere. Ancelle. MMWR. B. S. Rrookmeyer. Dessi. 337. the rate of progression to Thakrar. 9 0 0 5 8 (K. A. 27-30.R. D. 3 5 . R. 277-280.. This paper is a report from the European and Mediterra- Rebulla. M. ii. Angastinio. ( 1989) Censoring in an epidemic with (whether homosexual or haemophiliac): in our study.. 81 3. L. the results on Biotnetrics. existence of a n acute episode were obtained retrospectively.O. New England journal ofMedicine. AIDS. et a1 (1989) The natural history of Darby et al. age.. I. This finding contradicts that of Landonio et al syndrome in two thalassemicpatients after LAV contamination by (1988). Aledort.. the estimates found were J. Mary. Working Group on Haemoglobinopathies (1987) HIV a more important factor than the kind of contaminated blood infection in polytransfused thalassaemia patients. R. S. Barbarano. on behalfof the European and Mediterranean patients contaminated through blood transfusion. 1989: Lee ct al. Stratton.Borgna-Pignatti. 1989: Downs et al. Statistics in Medicirw. 312.... the same range at 3 years and a t 5 years although in our Goedert.