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Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort

van Lelyveld, Steven F.L.a; Gras, Luukb; Kesselring, Anoukb; Zhang, Shuangjieb; De Wolf, Frankb; Wensing, Annemarie M.J.c; Hoepelman, Andy I.M.aon behalf of the ATHENA national observational cohort study

doi: 10.1097/QAD.0b013e32834f32f8

Objective: We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART).

Design: Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml).

Methods: Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/μl (group A), 200–350 cells/μl (group B), 351–500 cells/μl (group C) or more than 500 cells/μl (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs).

Results: Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.33–0.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.14–0.86)].

Conclusion: Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients.

aDepartment of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht

bStichting HIV Monitoring, Amsterdam

cDepartment of Virology, Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Correspondence to Steven F.L. van Lelyveld, Department of Internal Medicine & Infectious Diseases, Huispostnummer F.02.126, Postbus 85500, 3508 GA Utrecht, The Netherlands. Tel: +31 88 7556228; e-mail:

Received 7 September, 2011

Revised 11 November, 2011

Accepted 14 November, 2011

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The introduction of HAART has improved the mortality and morbidity of patients infected with HIV-1 dramatically [1]. As a result, life expectancy in specific subgroups of HIV-infected patients is comparable with those having other chronic medical diseases (e.g. insulin-treated diabetes) [2] and in some cohorts even approaches that of the general population [3,4] Still, the incidence of non-AIDS-defining diseases (non-ADDs) such as cardiovascular events (CVEs) and non-AIDS defining malignancies (non-ADMs) [5,6] is higher in HIV-infected patients than in the general population.

Generally, treatment of HIV infection with HAART suppresses viral replication, leading to recovery of CD4+ T cells (CD4 cells). Unfortunately, in 9–29% of the patients, treatment with HAART fails to achieve an adequate CD4 cell count despite virological suppression [7–12], known as ‘immunological nonresponse’.

Several studies show a poorer long-term clinical outcome in terms of death, AIDS-defining diseases and non-ADDs, in patients with an inadequate immunological response on HAART [7,8,10,13]. However, these studies are limited due to sample size and/or do not have non-ADDs such as CVEs or non-ADMs as solitary endpoints.

Therefore, we set out to assess predictors and long-term clinical outcome – in particular, the occurrence of CVEs and non-ADM – in patients with a poor immunological recovery (low CD4 cell count) despite 2 years of virological successful HAART in the Dutch ATHENA cohort.

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Patients were included from the observational AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort, which follows HIV-positive patients who are registered in one of the 25 designated treatment centers in the Netherlands. Clinical data of patients who have decided not to opt out are anonymously recorded in a central database that is maintained by the Stichting HIV Monitoring [14]. The ATHENA database includes information on patient demographics, immunological and virological parameters, detailed treatment data, data on adverse events and AIDS-defining and selected non-AIDS-defining clinical events. Data on malignancies have been collected since 1998, on CVEs since 2000 and on liver disease since 2002. Data on CVEs and non-ADMs are collected according to the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study protocol ( Cardiovascular risk factors such as family history for cardiovascular disease and smoking (having a history of smoking, no amount specified), as well as alcohol abuse [>28 glasses per week (men), >21 glasses per week (women)] are recorded.

Inclusion criteria for this study were as follows: naive for antiretroviral therapy at the start of HAART (in or after 1998) at a minimal age of 16 years, at least two CD4 cell count measurements available between 1 and 2 years after starting HAART of which one between 1.5 and 2 years, observed suppression of viral load to less than 500 plasma HIV-RNA copies/ml within 9 months after starting HAART and plasma HIV-RNA viral load of less than 500 copies between 1.5 and 2 years after starting HAART. Exclusion criteria were as follows: therapy interruptions longer than 2 weeks during the first 2 years after starting HAART, pregnancy 10 months prior to starting HAART until end of follow-up, the combined use of tenofovir and didanosine and the use of immunosuppressive co-medication during the first 2 years after starting HAART.

Baseline was defined as 2 years after starting HAART. Patients were categorized into four groups based on their last two CD4 cell counts: group A with CD4 cell count less than 200 cells/μl (both measurements below 200 cells/μl), group B with CD4 cell count between 200 and 350 cells/μl (one or both measurements above 200 cells/μl and below or equal to 350 cells/μl), group C with CD4 cell count between 351 and 500 cells/μl (one or both measurements above 350 cells/μl and both below or equal to 500 cells/μl) and group D with CD4 cell count more than 500 cells/μl (both measurements above 500 cells/μl). Hepatitis C infection at baseline was defined as positive result on a quantitative or qualitative hepatitis C virus (HCV) RNA test or, if not available, positive HCV serology at baseline. Hepatitis B infection was defined as positive result on a hepatitis B surface antigen (HBsAg) test. Individuals were censored at their data of death or at the date of the last available plasma HIV-RNA measurement before 1 March 2009.

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The endpoints of this study were a composite endpoint [CVEs, all malignancies (except basal cell carcinoma), liver cirrhosis, AIDS or death], non-ADDs (non-ADM, liver cirrhosis and CVEs), CVEs and non-ADM. CVE was defined as a coronary bypass, coronary stenting and/or angioplasty, fatal and nonfatal myocardial infarction and cerebrovascular attack (CVA). Non-ADM was defined as any malignancy except Kaposi sarcoma, cervix carcinoma, non-Hodgkin lymphoma and basal cell carcinoma of the skin. Liver cirrhosis diagnosis was based on either histology or radiological reports.

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Statistical methods

A logistic regression model was used to analyze the association between patient, clinical and HAART regimen characteristics and poor immunological recovery (CD4 cell count <200 cells/μl despite 2 years of virological successful HAART, group A). Independent variables included age, sex, smoking, HCV co-infection, alcohol abuse, time on protease inhibitor-based regimen, plasma HIV-RNA at start of HAART, HIV transmission category [homosexual/heterosexual, intravenous drug use (IDU)], region of origin (western Europe/North America, sub-Saharan Africa, Caribbean/Latin America) and nadir CD4 cell count before the start of HAART (nadir CD4).

Differences in time to endpoints after baseline during follow-up between patient groups were analyzed using Kaplan–Meier survival estimates and unadjusted and adjusted Cox proportional hazards models. Time to the composite endpoints was defined as the time between baseline and first occurrence of any of the individual endpoints.

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Baseline characteristics and degree of immunological recovery

The characteristics of the 3068 selected patients are shown in Table 1, according to the groups of CD4 cell count recovery after 2 years of HAART.

Table 1

Table 1

The majority of the study population was men (83.4%) of western European or North American (65.0%) origin with a median age of 41 years. Most patients had acquired HIV through homosexual contact (57.5%). Total duration of follow-up after baseline was 10 956 patient-years. On the basis of the last two CD4 cell counts between 1 and 2 years after starting HAART, 199 (6.5%) patients were categorized into group A, 645 (21.0%) into group B, 1413 (46.0%) into group C and 811 (26.4%) into group D. At that time, 86.8% of patients had a plasma viral load of less than 50 copies/ml, whereas 13.2% had a viral load below 500 copies/ml. The median number of plasma HIV-RNA measurements per patient between start of HAART and baseline was 8 [interquartile range (IQR) 7–10].

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Predictors for poor immunological recovery

Out of 733 patients with a nadir CD4 of 0–50 cells/μl, 139 (19.0%) had a poor immunological recovery (group A) compared with 30 (8.6%) out of 351 patients with a nadir of 51–100 cells/μl and 28 (3.5%) out of 808 patients with a nadir of 101–200 cells/μl.

Older age was an independent predictor for a poor immunological recovery (Table 2), whereas higher nadir CD4 (nadir CD4 of 101–200 compared with 0–50 cells/μl) and a higher plasma HIV-RNA at the start of HAART (>5.0 log copies/ml compared with <4.0 log copies/ml) was associated with a better immunological outcome [adjusted odds ratio (aOR) 0.13 (95% confidence interval [CI] 0.08–0.20) and aOR 0.50 (95% CI 0.27–0.91), respectively]. The length of use of different drug classes during the first 2 years after starting HAART was not independently associated with poor immunological recovery [13–24 months protease inhibitor use compared with 0 months protease inhibitor use (24 months of mainly non-nucleoside reverse transcriptase inhibitor based HAART), aOR 0.79 (95% CI 0.55–1.13)]. Results were similar when protease inhibitor use was divided into boosted and unboosted protease inhibitor use (data not shown).

Table 2

Table 2

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CD4 cell count restoration after baseline

The CD4 cell count restoration after baseline was significantly different between the various groups (Fig. 1). Five years after baseline (7 years after initiation of HAART), the median CD4 cell count was 320 (IQR 240–410) for group A, 410 (IQR 323–510) for group B, 580 (IQR 450–710) for group C and 788 (IQR 630–1000) for group D (overall P < 0.0001).

Fig. 1

Fig. 1

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Morbidity and mortality in relation to degree of immunological recovery

During follow-up, 213 patients reached the composite endpoint. Most events were observed in the group with poorest immunological recovery; the Kaplan–Meier estimate of the percentage of patients in group A with an event within 5 years after baseline was 17.2%, compared with 10.7% (B), 10.4% (C) and 7.3% (D), overall log rank, P < 0.0001 (Fig. 2a). In unadjusted Cox proportional hazard models a significant lower risk for an event was found in those patients with higher CD4 cell counts after 2 years of HAART (Table 3). After adjustment for age and other baseline confounders, the hazard ratio of an event attenuated. Differences in the hazard of an event between groups D and A remained significant and the differences between B, C and A were borderline significant (overall P = 0.09). Older age, smoking, acquisition of HIV infection by IDU and the occurrence of non-AIDS-defining event before baseline (CVE, non-ADM or liver cirrhosis) were independently associated with the occurrence of an event.

Fig. 2

Fig. 2

Table 3

Table 3

One hundred and twelve patients reached the composite endpoint of non-ADDs. Most events occurred in group A; the Kaplan–Meier estimate for an event within 5 years was 10.9% for group A, compared with 5.6% (B), 4.9% (C) and 4.4% (D), overall log rank, P = 0.002 (Fig. 2b). In unadjusted models, the risk for an event was significantly higher in group A than in all the other groups [Table 3, hazard ratio of group D compared with that of group A: 0.34 (95% CI 0.19–0.63)]. Adjusted for age and other confounders (IDU, sex, smoking, alcohol abuse, region of origin, occurrence of a non-ADD before baseline and HCV co-infection), the hazard ratios comparing groups B–D with group A remained well below 1, but the 95% CI included 1 [hazard ratio of group D compared with that of group A: 0.58 (95% CI 0.31–1.07)]. Older age, IDU and a non-ADD diagnosis before baseline were independent predictors for the occurrence of a new non-ADD.

During follow-up, 57 patients experienced a CVE, consisting of 22 myocardial infarctions (six fatal), 14 CVAs (one fatal), 20 coronary stenting and/or angioplasty procedures and one coronary bypass procedure. The Kaplan–Meier estimate for a CVE (Fig. 2c) within 5 years was significantly higher in group A (4.7%) compared with the other groups [2.2% (B), 2.6% (C) and 2.0% (D); overall log rank, P = 0.01]. In unadjusted models, the risk for a CVE was significantly higher in group A compared with all other groups [Table 3; hazard ratio of group D compared with that of A: 0.31 (95% CI 0.13–0.70)]. The risk for CVE attenuated slightly in adjusted models, the hazard ratio of group B compared with that of A changed from 0.30 (95% CI 0.12–0.74) in an unadjusted analysis to 0.34 (95% CI 0.14–0.85) in adjusted analysis. Other independent predictors for a CVE were older age and the occurrence of a CVE before baseline. The variables sex, family history of cardiovascular event and smoking were included in the model as well.

Forty-one patients developed a non-ADM during follow up. Recorded were six anal malignancies, five Hodgkin lymphomas, four breast cancers, five lung cancers, two prostate cancers, two pharyngeal malignancies and 17 malignancies of other or unknown type. The Kaplan–Meier estimate for a non-ADM event within 5 years was highest in group A [4.3% compared with 2.1% (B), 1.4% (C) and 1.8% (D), overall log rank, P = 0.26 (Fig. 2d)]. Differences in the occurrence of non-ADM between groups in unadjusted analyses were borderline not significant (compared with group A, P = 0.05 for group C and P = 0.10 for group D). In adjusted models (for age, alcohol abuse, smoking), low CD4 cell counts were not significantly associated with the occurrence of a non-ADM (Table 3). Age and alcohol abuse were independently associated with the occurrence of non-ADM.

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The principal finding of this study is that antiretroviral-naïve patients with a poor immunological recovery despite virological successful HAART are at higher risk for morbidity and mortality and for cardiovascular complications in particular. Older age, low nadir CD4 cell count and low plasma HIV-RNA at the start of HAART were factors associated with a poor immunological recovery.

A significant proportion of patients in our study (27.5%) failed to reach a CD4 cell count of 350 cells/μl after 2 years of virological successful HAART. Moreover, even after 7 years of HAART, the median CD4 cell count [320 (IQR) 240–410] in this group remained well below 500 cells/μl. We found that lower CD4 cell nadir before the start of HAART and older age were predictors for poor immunological recovery at 2 years, in line with previous reports [7–10,15]. Moreover, we found that a high plasma viral load (>5.0 log10 copies/ml) at the start of HAART was associated with a better immunological outcome, as was reported in other studies [10,16–18]. The reasons for this correlation have not yet been clearly elucidated. Reduced thymic function, increased immune activation leading to lymphoid tissue fibrosis and T-cell apoptosis and human genetic polymorphisms are other factors reported to be involved in the mechanism of a poor immunological response [19–23]. We did not find an association between immunological recovery after 2 years of HAART and the use of protease inhibitors or HCV co-infection, in contrast to other studies [7,8,16]. Concerning the latter, this might be related to the low overall prevalence of HCV co-infection in our study (4.7%), whereas investigators who found a relation between HCV co-infection and poor immunological recovery reported a much higher prevalence (33.0%) [16].

In our study, patients with low CD4 cell counts after 2 years of virological successful HAART more often experienced fatal and nonfatal diseases (combined endpoint of death, AIDS-defining diseases, malignancies, cardiovascular disease and liver cirrhosis). In addition to the degree of immunological recovery, known risk factors such as older age, smoking, alcohol abuse and IDU acquisition of HIV infection were independent predictors. The higher risk for these diseases in these patients can be partly explained by their average older age in our study. However, even after adjusting for age, there was a significant association between a poor immunological recovery and an increased risk for events.

We analyzed the occurrence of non-ADDs as a combined endpoint, and likewise found more events in the groups with lower degrees of immunological recovery. In models adjusted for age and other confounders, we found a trend toward lower risk for non-ADD in patients with better immunological recovery after 2 years of virological successful HAART. Studies have shown that low CD4 cell counts are not only related to the incidence of AIDS-defining diseases, but are also associated with non-ADDs [6,24–27]. Associations between most recent CD4 cell count and the occurrence of cardiovascular disease [27–29], liver disease [30] and non-AIDS-related malignancies [26] have been reported. Whereas other studies have reported data on mortality or combined endpoints of AIDS and non-ADDs in patients with a poor immunological response on HAART [7,8,10,13], we are the first to report data on non-ADDs as a solitary endpoint in these patients.

Patients with a poor immunological recovery after 2 years of HAART were at a higher risk for CVEs, for a large part because of their older age. In age-adjusted analyses (Table 3), we found that differences between the group with poorest immunological recovery (A) and groups B–D in the risk for a CVE remained large. However, this difference was significant for group B only, whereas a trend was found for the other groups. Larger studies are necessary to confirm the finding of an increased risk for CVEs in patients with low CD4 cell counts despite virological successful HAART. Chronic HIV infection has now been recognized as a risk factor for cardiovascular disease [31]. Several studies report a relationship between low CD4 cell counts and occurrence of CVEs; Triant et al.[28] reported low CD4 cell count as an independent predictor for myocardial infarction, whereas data of the HIV Outpatient Study (HOPS) showed a relationship between latest CD4 cell count and cardiovascular disease [29]. Other studies found a relationship between the degree of immune activation, chronic inflammation and vascular dysfunction [32]. Moreover, the level of immune activation and chronic inflammation is reported to be higher in patients with a poor immunological response on HAART [33], despite viral suppression. Therefore, a high level of immune activation in these patients could play a role in the development of cardiovascular complications.

In univariate analysis, we found a trend for the occurrence of more non-ADM in the group with the lowest degree of immunological recovery. It has been suggested that (duration of exposure to) immunodeficiency is related to the occurrence of non-ADM, as several studies have shown that both nadir CD4 cell count and current CD4 cell count are associated with a higher frequency of non-ADM [6,26]. However, these studies have included both antiretroviral-treated and antiretroviral-untreated patients in their analysis, whereas patients in our study were included only if treatment with HAART resulted in virological success. In adjusted analysis, we did not find an association between CD4 cell count after 2 years of HAART and the occurrence of non-ADM. Due to the low number of endpoints (41 non-ADMs), the power of this study to answer this question might be limited.

The findings of the present study emphasize the importance of starting HAART at higher CD4 cell counts, in line with evidence that initiation of HAART at higher CD4 cell counts reduces mortality [34]. Moreover, as 31–39% of newly diagnosed HIV-infected patients in western Europe present with a CD4 cell count less than 200 cells/μl [35], these data suggest that more aggressive screening policies may need to be implemented.

Strengths of this study include the use of a well defined cohort followed prospectively wherein data are recorded in a standardized manner and the large number of patients included in this study. However, there are limitations as well. In some patients, information on traditional risk factors was missing and the data on conditions related to cardiovascular diseases such as blood lipids, hypertension and renal function were not included in this study. Furthermore, probably an even larger sample size might be necessary to confirm whether the association between persistent low CD4 cell counts on HAART and long-term clinical complications (especially for non-ADDs) is independent of older age. Finally, occurrence of CVE and non-ADM might be related to the duration of HIV infection as HIV-associated biomarkers such as CD4 cell count nadir and markers of inflammation have been associated with an elevated risk of CVEs [36]. We did not control for duration of (known) HIV infection or nadir CD4 cell count. As nadir CD4 cell count is strongly correlated with the degree of immunological recovery after 2 years of HAART, a larger sample size would be necessary to disentangle these two effects as well.

In conclusion, our findings clearly stress the importance of achieving an adequate restoration of the immune system to minimize the risk of serious diseases such as CVEs. Our data suggest that starting HAART at higher CD4 cell counts, especially in older aged patients, may be beneficial. Further investigations are necessary to identify new immune-modulating therapeutic options for patients in whom HAART fails to achieve an adequate restoration of the immune system.

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The ATHENA national observational cohort has been made possible through the collaborative efforts of the following physicians (* site coordinating physicians): Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam: Prof. Dr J.M. Prins*, Prof. Dr T.W. Kuijpers, Dr H.J. Scherpbier, Dr K. Boer, Dr J.T.M. van der Meer, Dr F.W.M.N. Wit, Dr M.H. Godfried, Prof. Dr P. Reiss, Prof. Dr T. van der Poll, Dr F.J.B. Nellen, Prof. Dr J.M.A. Lange, Dr S.E. Geerlings, Dr M. van Vugt, Drs D. Pajkrt, Drs J.C. Bos, Drs M. van der Valk, Drs M.L. Grijsen, Dr W.J. Wiersinga. Academisch Ziekenhuis Maastricht, Maastricht: Dr G. Schreij*, Dr S. Lowe, Dr A. Oude Lashof. Catharina-ziekenhuis, Eindhoven: Drs M.J.H. Pronk*, Dr B. Bravenboer. Erasmus Medisch Centrum, Rotterdam: Dr M.E. van der Ende*, Drs T.E.M.S. de Vries-Sluijs, Dr C.A.M. Schurink, Drs M. van der Feltz, Dr J.L. Nouwen, Dr L.B.S. Gelinck, Dr A. Verbon, Drs B.J.A. Rijnders, Dr L. Slobbe, Dr E.C.M. van Gorp. Erasmus Medisch Centrum–Sophia, Rotterdam: Dr N.G. Hartwig, Dr G.J.A. Driessen. Flevoziekenhuis. Almere: Dr J. Branger*. HagaZiekenhuis, Den Haag: Dr E.F. Schippers*, Dr C. van Nieuwkoop. Isala Klinieken, Zwolle: Dr P.H.P. Groeneveld*, Dr M.A. Alleman, Drs J.W. Bouwhuis. Kennemer Gasthuis: Prof. Dr R.W. ten Kate*, Dr R. Soetekouw. Leids Universitair Medisch Centrum, Leiden: Dr F.P. Kroon*, Prof. Dr P.J. van den Broek, Prof. Dr J.T. van Dissel, Dr S.M. Arend, Drs C. van Nieuwkoop, Drs M.G.J. de Boer, Drs H. Jolink. Maasstadziekenhuis, Rotterdam: Dr J.G. den Hollander*, Dr K. Pogany. Medisch Centrum Alkmaar, Alkmaar: Drs G. van Twillert*, Drs W. Kortmann*. Medisch Centrum Haaglanden, Den Haag: Dr R. Vriesendorp*, Dr E.M.S. Leyten, Dr L.B.S. Geelink. Medisch Spectrum Twente, Enschede: Dr C.H.H. ten Napel*, Drs G.J. Kootstra. Onze Lieve Vrouwe Gasthuis, Amsterdam: Prof. Dr K. Brinkman*, Dr W.L. Blok, Dr P.H.J. Frissen, Drs W.E.M. Schouten, Drs G.E.L. van den Berk. Sint Elisabeth Ziekenhuis, Tilburg: Dr J.R. Juttmann*, Dr M.E.E. van Kasteren, Drs A.E. Brouwer. Sint Lucas Andreas Ziekenhuis, Amsterdam: Dr J. Veenstra*, Dr K.D. Lettinga. Slotervaartziekenhuis, Amsterdam: Dr J.W. Mulder*, Drs P.M. Smit, Drs S.M.E. Vrouenraets, Dr F.N. Lauw. Stichting Medisch Centrum Jan van Goyen, Amsterdam: Drs A. van Eeden*, Dr D.W.M. Verhagen*. Universitair Medisch Centrum Groningen, Groningen: Drs H.G. Sprenger*, Drs R. Doedens, Dr E.H. Scholvinck, Drs S. van Assen, Dr W.F.W. Bierman. Universitair Medisch Centrum Sint Radboud, Nijmegen: Dr P.P. Koopmans*, Prof. Dr R. de Groot, Dr M. Keuter, Dr A.J.A.M. van der Ven, Dr H.J.M. ter Hofstede, Dr M. van der Flier, Drs A.M. Brouwer, Dr A.S.M. Dofferhoff. Universitair Medisch Centrum Utrecht, Utrecht: Prof. Dr A.I.M. Hoepelman*, Dr T. Mudrikova, Dr M.M.E. Schneider, Drs C.A.J.J. Jaspers, Dr P.M. Ellerbroek, Dr J.J. Oosterheert, Dr J.E. Arends, Dr M.W.M. Wassenberg, Dr R.E. Barth. Vrije Universiteit Amsterdam, Amsterdam: Dr M.A. van Agtmael*, Drs J. de Vocht, Dr R.M. Perenboom, Drs F.A.P. Claessen, Drs E.A. bij de Vaate. Wilhelmina Kinderziekenhuis, Utrecht: Dr S.P.M. Geelen, Dr T.F.W. Wolfs, Dr L.J. Bont. Ziekenhuis Rijnstate, Arnhem: Dr C. Richter*, Dr J.P. van der Berg, Dr E.H. Gisolf. Admiraal De Ruyter Ziekenhuis, Vlissingen: Drs M. van den Berge*, Drs A. Stegeman. Medisch Centrum Leeuwarden, Leeuwarden: Dr M.G.A. van Vonderen*, Drs D.P.F. van Houte. Sint Elisabeth Hospitaal, Willemstad - Curaçao: Dr C. Winkel, Drs F. Muskiet, Drs Durand, Drs R. Voigt.

Author contributions: S.F.L.L. designed the study, performed research, analyzed data and wrote the manuscript. L.G. contributed to the design of the study, the analysis of the data and the writing the manuscript. S.Z. contributed to writing of the manuscript. A.K. contributed to interpretation of the analysis and writing of the manuscript. F.W. contributed to the study design. A.M.J.W. contributed to the study design, interpretation of the data and writing of the manuscript. A.I.M.H. was responsible for overall supervision of the study, designed the study, contributed to interpretation of the data and writing of the manuscript.

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Conflicts of interest

S.F.L.L. has received financial support for research, travel, speaking engagements or consultancy from BMS, GSK, Pfizer, Roche, Tibotec and ViiV healthcare; A.M.J.W. from Abbott, BMS, Gilead, MSD, Pfizer, Tibotec and ViiV healthcare. A.I.M.H. is a member of the advisory board of BMS, Gilead, ViiV healthcare, Janssen and MSD and has received financial grant support from Pfizer, MSD, Roche and Gilead. L.G., A.K. and F.W. have received no financial support.

Financial support: The ATHENA national observational cohort is maintained by the HIV Monitoring Foundation, supported by the Dutch Ministry of Health.

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AIDS; cardiovascular diseases; CD4 lymphocyte count; HAART; HIV; neoplasms

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