Anaemia has been widely reported to predict a poorer prognosis for HIV-infected patients, both in terms of progression to AIDS and in survival, independent of the CD4 lymphocyte count [1-12]. In recent studies, viral load has been shown to be highly prognostic for AIDS and death [13-16], but the prognostic value of haemoglobin level in addition to the information provided by CD4 lymphocyte count and viral load has yet to be determined.
Earlier studies have tended to concentrate on a single measurement of haemoglobin and CD4 lymphocyte count, and few have used serial measurements of both markers to determine their joint prognostic value . To our knowledge, none of these previous studies have incorporated information from viral load. A number of studies have described serial measurements of CD4 lymphocyte counts and estimated the rate of CD4 lymphocyte decline [18-23], but the pattern of change in haemoglobin during HIV infection has not been described.
The aim of this study was, therefore, to determine the pattern of changes in haemoglobin over time among patients recruited to EuroSIDA. We sought to compare the rate of change in haemoglobin levels in patients who died with those in patients who did not die. In addition, we sought to investigate the prognostic value of haemoglobin and CD4 lymphocyte count. A substantial subset of patients additionally had data on viral load, and in these patients we determined the joint prognostic value of the latest value of haemoglobin, viral load and CD4 lymphocyte count.
Subjects and methods
The EuroSIDA study is a prospective, European study of patients with HIV in 52 centres across Europe (including Israel, see Appendix). Details of the study have been published [24,25]. In brief, centres provided data on consecutive patients seen in the outpatient clinic from 2 May 1994 until a predefined number of patients was enrolled from each centre. This cohort of 3120 patients was defined as the EuroSIDA I cohort. Enrolment of a second cohort of 1367 patients began in December 1995. A further 2846 patients were recruited from April 1997 and was defined as the EuroSIDA III cohort. Information from up to eight follow-up visits is available from cohort I, up to five visits for cohort II and two for cohort III.
Eligible patients were those with a CD4 lymphocyte count below 500¥106 cells/l in the previous 4 months, and older than 16 years at the time of enrolment. Information was collected from patient case notes and by patient interview onto a standardized data collection form at baseline and every 6 months thereafter. At each follow-up visit, the latest haemoglobin measurement is requested, as are details on all CD4 lymphocyte counts measured since last follow-up and information on viral load measurements, including the method used and the lower limit of detection. Details of specific methodology, time of day of the sampling, precision of measurements or variability of measurements within or among centres are not available. For each patient, the date of starting and stopping each antiretroviral drug was recorded, as was the use of drugs for prophylaxis against opportunistic infections. Dates of diagnosis of all AIDS-defining diseases have also been recorded, using the 1993 clinical definition of AIDS from the Centers for Disease Control and Prevention . Members of the coordinating office visited all centres to ensure correct patient selection and that accurate data was provided.
All patients with at least one haemoglobin value and CD4 lymphocyte count measured during prospective follow-up were included in the present analysis. Values of the haemoglobin and CD4 lymphocyte count at baseline were compared across demographic groups using chi squared tests and non-parametric tests such as the Kruskall-Wallis test.
At each 6-month time point following recruitment, the change in median haemoglobin value from the value at recruitment was calculated using linear interpolation. Methods of linear regression were used to estimate the annual rate of change in haemoglobin following recruitment to EuroSIDA among those patients with three or more haemoglobin measurements before death, and multiple linear regression was used to determine which factors were related to the rate of change in haemoglobin.
Standard Kaplan-Meier techniques  were used to investigate the proportion of deaths among three groups of patients. We defined a normal level of haemoglobin as greater than 14g/dl for men and greater than 12g/dl for women . Mild anaemia was defined as a haemoglobin level of 8-14g/dl for men, and 8-12g/dl for women. Severe anaemia was defined as a haemoglobin level of less than 8g/dl for both males and females. Cox proportional hazard models were used to determine the relationship between CD4 lymphocyte count and haemoglobin as prognostic markers for death . Both markers were modelled as time-dependent covariates to determine if serial measurements of haemoglobin provide prognostic information. For the subset of patients with viral load data available, the joint prognostic value of the three markers was determined. Various transformations of the markers were considered (log, square root, etc.) to determine which provided the best fitting model. All analyses were performed using SAS version 6.12 . A P values of less than 0.05 was considered significant, and all tests of significance were two sided.
In total, 6725 patients had both a CD4 lymphocyte count and haemoglobin value available at recruitment to EuroSIDA. These patients are described in Table 1. There were 505 patients for whom there was no baseline measurement of haemoglobin. These patients were similar to the patients included in this analysis in terms of gender, race, age and exposure category but were significantly more likely to be from Southern Europe (P<0.001), have an AIDS diagnosis at recruitment (P<0.001) and to have a CD4 lymphocyte count below 200¥106 cells/l at recruitment (P=0.002). There was a moderate correlation between haemoglobin and CD4 lymphocyte count at recruitment to EuroSIDA (correlation coefficient, 0.249; P<0.0001) and considerable differences between demographic groups at recruitment, both in their haemoglobin level and their CD4 lymphocyte count (Table 1).
At recruitment to EuroSIDA, 2716 patients (40.4%) had a normal level of haemoglobin, 3917 patients (58.2%) had mild anaemia and 92 patients (1.4%) had severe anaemia (Table 2). Patients with severe anaemia were significantly more likely to have a CD4 lymphocyte count of 50¥106 cells/l or lower (P<0.001, chi-squared test). Patients with mild or severe anaemia were significantly more likely to have taken zidovudine at some stage (P<0.001, chi-squared test). In addition, patients with anaemia, mild or severe, were much more likely to have been diagnosed with AIDS in the 6 months prior to recruitment to EuroSIDA (P<0.001, chi-squared test).
There were 3008 patients with three or more serial measurements of haemoglobin during follow-up for whom an annual rate of change of haemoglobin could be estimated by linear regression. Among all patients, the change in haemoglobin per calendar year was minimal [+0.06g/dl; interquartile range (IQR) -1.13 to +1.35g/dl]; 1557 patients (51.8%) had an increasing haemoglobin level. However, among patients who did not die, the median annual change in haemoglobin was +0.25g/dl (IQR -0.63 to +1.48g/dl); 2448 patients (58.1%) had a haemoglobin level that was increasing during follow-up. In contrast, among patients who died, the median annual change in haemoglobin was -2.41g/dl (IQR -6.55 to 0.00g/dl) and just 134 patients (23.9%) had increasing haemoglobin levels. This difference was statistically significant (P<0.0001, Wilcoxon test). After adjustment for demographic variables, the baseline CD4 lymphocyte count, haemoglobin level, and AIDS status at recruitment, those patients who died had a statistically significant faster decline in haemoglobin than patients who did not die (P<0.0001). There was no association between haemoglobin level at death and cause of death.
The proportions of patients with anaemia differed after starting a highly active antiretroviral treatment (HAART) regimen among a subset of 1624 patients who started HAART during prospective follow-up. Before HAART was initiated, 34.5% of patients had no anaemia, 64.0% had mild anaemia and 1.5% had severe anaemia, while at 6 months into HAART therapy these proportions had changed to 46.8, 52.0 and 1.2% and at 12 months were 53.8, 45.6 and 0.6%, respectively.
As described in the Methods, three groups of patients were created based on their haemoglobin value at recruitment: normal, mild and severe anaemia. Figure 1 presents the Kaplan-Meier estimates of the proportion of patients who have died. In the category of severe anaemia, there were less than 20 patients left under follow-up after 12 months and hence this curve has been truncated at 12 months. At 12 months, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% CI 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6). The difference between the three groups was highly statistically significant (P<0.0001, log-rank test).
Both haemoglobin and CD4 lymphocyte count were strongly related to the risk of death in univariate Cox proportional hazards models (Table 3). In the first instance, both markers were included in all Cox models shown as time-dependent covariates, which used the latest value of the markers to estimate the risk of death. In a multivariate model (stratified for clinical centre and adjusted for demographic factors such as age, gender and risk group, treatment and AIDS as time-dependent variables), both haemoglobin and CD4 lymphocyte count were independently related to the risk of death. The relative hazard of death (RH) associated with a 1g/dl decrease in haemoglobin was 1.39 (95% CI 1.34-1.43; P<0.0001) and the RH associated with a 50% difference in CD4 lymphocyte count was 1.36 (95% CI 1.31-1.41; P<0.0001).
In a clinical situation, more useful information may be provided by using discrete cut-offs of these markers to make decisions about monitoring patients and for guiding treatment decisions. We therefore, repeated the Cox model above using three categories for both CD4 lymphocyte count and haemoglobin (>200¥106 cells/l, 51-200¥106 cells/l and 50¥106 cells/l or less; normal haemoglobin, mild anaemia and severe anaemia). These categories were then modelled as time dependent in a similar multivariate model to that presented in Table 3. The RH values from this model are shown in Fig. 2 and are expressed relative to a person with a CD4 lymphocyte count of over 200¥106 cells/l and a normal haemoglobin level. The RH clearly increases exponentially as either the CD4 lymphocyte count falls or as anaemia develops. For example, among patients with a CD4 lymphocyte count of over 200¥106 cells/l, patients with severe anaemia were at almost 30 times the risk of death compared with patients without anaemia (RH 29.0; 95% CI 9.2-91.4; P<0.0001). Patients without anaemia but with CD4 lymphocyte counts of 50¥106 cells/l or less were at 14 times the risk of death compared with patients with CD4 lymphocyte counts of 200¥106 cells/l or more (RH 14.4; 95% CI 7.9-26.2; P<0.0001). Patients with severe anaemia and a CD4 lymphocyte count of 50¥106 cells/l or less were at 90 times the risk of death compared with patients with a normal haemoglobin level and a CD4 lymphocyte count of over 200¥106 cells/l (RH 90.1; 95% CI 49.0-165.6; P<0.0001).
There were 164 deaths among 4707 patients with at least one prospective measurement of viral load. The logarithm (base 10) of viral load was also included in Cox proportional hazards models as a time-updated covariate, as shown in Table 4. Although there were less patients included in the analyses and less endpoints, the current level of haemoglobin remained a statistically significant prognostic marker for death after adjustment for the current CD4 lymphocyte count and viral load measurement. In a multivariate model, after adjustment, the RH associated with a 1g/dl decrease in haemoglobin was 1.57 (95% CI 1.41-1.75; P<0.0001).
We found a strong relationship between haemoglobin, CD4 lymphocyte count and risk of death. These results are based on data from the EuroSIDA study, which is a prospective study across Europe of over 7000 patients with HIV; information on clinical diagnoses, haemoglobin, CD4 lymphocyte counts and viral load are collected at regular intervals. With in excess of 10000 person-years of follow-up, this large study has sufficient power to investigate the changes over time in haemoglobin and the association between death and the anaemia, CD4 lymphocyte count and viral load where this data was available.
Previous studies have shown that low haemoglobin levels increase the risk of AIDS [3,31], increase the risk of death in patients with AIDS [2,6,8,11] and increase the risk of death among patients with advanced immunodeficiency [1,12,32], both in cross-sectional [5,32] and longitudinal studies [1-3,6,11,12,31]. Several staging systems have suggested that important information can be provided by haemoglobin levels [1,11,12,31,33]. Our results show that haemoglobin levels provide prognostic information independent of that provided by the CD4 lymphocyte count. In addition, in a large subset of patients, we have shown for the first time that haemoglobin, CD4 lymphocyte count and viral load were all independent prognostic markers. We concentrated on death as the endpoint, but a similar prognostic value for AIDS was also found (data not shown).
In contrast to most previous work, we have used serial measurements to determine the risk of death associated with the latest measurement and shown that both laboratory markers provide important information. Using both continuous values of the markers and simple clinical cut-offs, we have demonstrated the large increased risk of death as the CD4 lymphocyte count declines, the haemoglobin level declines or as both move together. Although the cut-offs we have used to define anaemia differ from those in a recent paper by Moore et al., our results agree well with this recent study, which used the latest measure of haemoglobin and CD4 lymphocyte count in a similar way to the present analysis . The EuroSIDA study is multicentre, and we were not able to determine the possible effects of individual laboratory precision, variation or time of blood sample. We have, however, stratified our model for centre, which adjusts to some extent for possible differences between centres in the methodology of measuring the various laboratory values.
Before the introduction of HAART, investigators reported that the annual loss of CD4 lymphocyte counts was 40-80¥106 cells/l [19-23]. Measurement of the loss of haemoglobin during HIV infection has not previously been reported. It was interesting to note that the change in haemoglobin was gradual and a continual process. There have been considerable changes in the availability of antiretroviral regimens and in the way they are combined in the EuroSIDA study . There was preliminary evidence from this analysis that patients starting HAART were less likely to have anaemia following treatment, although the duration of follow-up was quite limited. The impact of these rises in haemoglobin on mortality after initiating HAART remains to be determined.
The pathogenesis of HIV-associated anaemia is unclear and is likely to be multifactorial in nature [35-37]. Possible causes are bleeding (gastrointestinal malignancy/severe infection), insufficient dietary intake (vitamins such as cobalamin and folate, iron, and general malnutrition), haemolytic anaemia (i.e. malignancies, infections, splenomegaly, immune dysfunction), changes in erythropoietin synthesis and/or bone marrow suppression. Suppression of the bone marrow in HIV-infected patients may be initiated in several ways. These include an action of HIV itself (infection of the progenitor of the red blood cell synthesis in late-stage disease), the use of antiretroviral drugs (primarily zidovudine), direct pathogenic involvement of the bone marrow (malignant lymphoma, atypical mycobacteriosis), prophylactic or therapeutic treatment against opportunistic diseases or malignancies (i.e. sulphamethoxazole, ganciclovir, methotrexate, adriamycin) or simply non-specific effects relative to chronic or acute infection.
We found that 78.2% of the patients with mild or severe anaemia at baseline had received zidovudine at some point, and 11.5 % had been diagnosed with AIDS less than 6 months prior to recruitment to EuroSIDA. The majority of patients with severe anaemia were no longer taking zidovudine. However, our data do not permit any conclusion on the causal relation between these parameters and the presence of anaemia. In addition, information regarding whether the patients received blood transfusion during follow-up was not collected. In order to study the prognostic value of anaemia on clinical prognosis further, a randomized controlled trial of recovery from anaemia is warranted, comparing the prognosis for anaemic HIV-infected patients receiving transfusion or not.
Haemoglobin is both easy and inexpensive to measure and is recorded within this study at 6-month intervals. Clearly, even with only twice yearly measures, patients who developed severe anaemia were at an increased risk of death. Monitoring haemoglobin levels could be used to alert clinicians to those patients who require more regular clinical follow-up or who may need treatment for their anaemia. Moore et al. found that treatment of anaemia with erythropoietin was associated with an improved prognosis , possibly by allowing higher doses or prolonged use of drugs such as zidovudine and ganciclovir. It is important to note that data on use of erythropoietin were not available for this analysis, nor were data on the frequency of transfusion for anaemia and its relationship with prognosis.
In a recent cross-sectional study, haemoglobin measurement was shown to play an important role in the basic management of HIV disease in West Africa . Given its strong relationship with AIDS-defining illness and death, haemoglobin levels could be measured easily where resources for more sophisticated laboratory markers such as viral load or even CD4 lymphocyte count were not available (given that measurement of the CD4 lymphocyte count requires flow cytometry, an expensive technique unavailable in many developing countries) . Regular measurements could help to determine which patients are at greatest risk of disease progression, allowing these patients to be identified for closer monitoring or therapeutic intervention. Other prognostic markers such as b2-microglobulin and neopterin [40,41] are also easily measured and may be useful for monitoring and assessing clinical prognosis together with haemoglobin.
In conclusion, we have shown that haemoglobin levels gradually decrease in HIV-infected patients who die. Haemoglobin remains a strong independent prognostic marker for death after adjustment for CD4 lymphocyte count and viral load. Therefore, among patients with similar CD4 lymphocyte counts and viral load measures, those patients with a lower haemoglobin level were at a significantly increased risk of death. Further follow-up is needed to determine the impact of new treatment regimens on levels of haemoglobin, whether the incidence of anaemia continues to decrease and to investigate whether an increase in haemoglobin decreases the risk of death.
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Members of the multicentre study group EuroSIDA
National coordinators are given in parentheses. Austria (N. Vetter): Pulmologisches Zentrum der Stadt Wien, Vienna. Belgium (N. Clumeck): P. Hermans, B. Sommereijns, Saint-Pierre Hospital, Brussels; R. Colebunders, Institut of Tropical Medicine, Antwerpen. Denmark (J. Nielsen): J. Lundgren, T. Benfield, O. Kirk, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, J. Wandall, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense. France (C. Katlama): C. Riviere, Hôpital de la Pitié-Salpétière, Paris; J-P. Viard, Hôpital Necker-Enfants Malades, Paris; T. Saint-Marc, Hôpital Edouard Herriot, Lyon; C. Pradier, Hôpital de l‚Archet, Nice. Germany (M. Dietrich): A. Wywiol, Bernhard-Nocht-Institut for Tropical Medicine, Hamburg; J. van Lunzen, Eppendorf Medizinische Kernklinik, Hamburg; V. Miller, S. Staszewski, JW Goethe University Hospital, Frankfurt; F.-D. Goebel, Medizinische Poliklinik, Munich. Greece (J. Kosmidis): P. Gargalianos, H. Sambatakou, Athens General Hospital, Athens; G. Stergiou, G. Panos, A. Papadopoulos, M. Astri, 1st IKA Hospital, Athens. Ireland (F. Mulcahy): St James‚s Hospital, Dublin. Israel (I. Yust): D. Turner, Ichilov Hospital, Tel Aviv; S. Pollack, Z. Ben-Ishai, Rambam Medical Center, Haifa; Z. Bentwich, Kaplan Hospital, Rehovot; S. Maayan, Hadassah University Hospital, Jerusalem. Italy (S. Vella, A. Chiesi): Istituto Superiore di Sanita, Rome; C. Arici, Ospedale Riunuti, Bergamo; R. Pristerá, Ospedale Generale Regionale, Bolzano; F. Mazzotta, F.Vichi, Ospedale S. Maria Annunziata, Florence; B. DeRienzo, A. Catania, Università di Modena, Modena; A. Chirianni, E. Montesarchio, Presidio Ospedaliero AD Cotugno, Naples; V. Vullo, P. Santopadre, Università di Roma La Sapienza, Rome; O. Armignacco, P. Franci, P. Narciso, M.A. Rosci, M. Zaccarelli, Ospedale Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; A. D‚Arminio Monforte, Osp. L Sacco, Milan. Luxembourg (R. Hemmer): T. Staub, Centre Hospitalier, Luxembourg. Netherlands (P. Reiss): Academisch Ziekenhuis bij de Universitet van Amsterdam, Amsterdam. Norway (J. Bruun): Ullevål Hospital, Oslo. Portugal (F. Antunes): Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; R. Proenca, Hospital Curry Cabral, Lisbon. Spain (J. González-Lahoz): R. Polo, Instituto Carlos III, Madrid; B. Clotet, A. Jou, J. Conejero, D. Tural, Hospital Germans Trias i Pujol, Badalona; J. Gatell, J. Miró, Hospital Clinic I Provincial, Barcelona. Sweden (A. Blaxhult): Danderyd Hospital, Danderyd; B. Heidemann, Södersjukhuset, Stockholm; P. Pehrson, Huddinge Sjukhus, Stockholm. Switzerland (B. Ledergerber): R. Weber, University Hospital, Zürich; P. Francioli, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, P. Sudre, Hospital Cantonal Universitaire de Geneve, Geneve. United Kingdom (S. Barton): St Stephen‚s Clinic, Chelsea and Westminster Hospital, London; A. Johnson, D. Mercy, Royal Free and University College London Medical School (University College Campus) A. Phillips, C. Loveday, M. Johnson, A. Mocroft (Royal Free Campus); A. Pinching, J. Parkin, Medical College of Saint Bartholomew‚s Hospital, London; J. Weber, D. Churchill, Imperial College School of Medicine at St Mary‚s, London; R. Brettle, City Hospital, Edinburgh.
Steering committee: J. Nielsen (chair), N. Clumeck, M. Dietrich, J. Gatell, A. Johnson, C. Katlama, B. Ledergerber, C. Loveday, A. Phillips, P. Reiss, S. Vella.
Coordinating centre staff : J. Lundgren (project leader), I. Gjørup, T. Benfield, O. Kirk, A. Mocroft, A. Sørensen, O. Eriksen, L. Teglbjærg.