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The role of antiretroviral therapy in the incidence of pancreatitis in HIV-positive individuals in the EuroSIDA study

Smith, Colette Ja; Olsen, Christian Hb; Mocroft, Amandaa; Viard, Jean Paulc; Staszewski, Schlomod; Panos, Georgee; Staub, Theresef; Blaxhult, Andersg; Vetter, Norberth; Lundgren, Jens Db

doi: 10.1097/QAD.0b013e3282f03094
Clinical Science

Aim: This study investigated the incidence of pancreatitis and its association with antiretroviral therapy (ART), focussing on stavudine and didanosine.

Methods: EuroSIDA has collected information on pancreatitis since Summer 2001. All identified cases have been verified by the coordinating centre. Individuals were followed from June 2001 or the date of entry into EuroSIDA (whichever occurred later) until a diagnosis of pancreatitis or the last study visit. Factors associated with pancreatitis were investigated using Poisson regression. Cumulative lengths of exposure to didanosine without stavudine, stavudine without didanosine, stavudine with didanosine, and other ART were time-updated variables. Treatment variables were fitted with a 6-month time lag.

Results: There were 43 (nine presumptive) pancreatic events in 9678 individuals during 33 742 person-years (incidence 1.27/1000 person-years). The incidence among those with no, 2 or less and over 2 years' exposure to ART including stavudine and didanosine was 1.24, 1.73 and 0.78/1000 person-years, respectively. In multivariable analysis, higher baseline CD4 cell counts were associated with a decreased risk of pancreatitis. There was no evidence of an association of pancreatitis with cumulative exposure to didanosine and stavudine, didanosine without stavudine, stavudine without didanosine, or other ART.

Conclusion: We observed a low overall rate of pancreatitis in the years 2001–2006, and did not find an association of an increased incidence of pancreatitis with cumulative exposure to antiretroviral agents generally, and to didanosine and stavudine in particular.

From the aRoyal Free and University College Medical School, London, UK

bCopenhagen HIV Program (CHIP), Copenhagen, Denmark

cHopital Necker-Enfants Malade, Paris, France

dJ.W. Goethe University Hospital, Frankfurt, Germany

e1st IKA Hospital Athens; Greece

fCentre Hospitalier de Luxembourg, Luxembourg, Luxembourg

gKarolinska University Hospital Solna, Sweden

hOtto Wagner Spital, Sanatoriumstrasse, Austria.

Received 26 March, 2007

Revised 18 June, 2007

Accepted 21 June, 2007

Correspondence to Colette J. Smith, Royal Free and University College Medical School, Hampstead Campus, Rawland Hill St, London UK NW3 2PF. Tel: +44(0) 2078302239; fax: +44(0) 2077941224; e-mail:

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The introduction of combination antiretroviral therapy (ART) in the mid-1990s in industrialized countries has led to dramatic reductions in morbidity and mortality among HIV-positive individuals [1,2]. There have, however, also been reports of long-term toxicities associated with use of these antiretroviral drugs, including an increase in the incidence of cardiovascular disease [3–5], hepatotoxicity [6,7] and renal disease [8,9]. Cases of pancreatitis have also been reported [10–15]. Previous studies have shown pancreatitis incidence rates varying from 0.03 [11] to 1.95 [10] per 100 person-years of follow-up. In those studies patients were exposed to a number of different antiretroviral drugs, and there were differences in the exact definition of pancreatitis used, which may account for such large differences.

It has been proposed that the nucleoside reverse transcriptase inhibitor (NRTI) class of antiretroviral agents in general, and the NRTIs stavudine and didanosine in particular, may lead to increased mitochondrial toxicity [16,17], which in turn may lead to a higher risk of pancreatitis [11–13,17]. Other studies, however, have not found such a link [10]. The aim of this study was twofold. We first investigated the incidence of pancreatitis among a large, well-characterized cohort of HIV-positive individuals, and second we assessed the factors associated with increased rates of pancreatitis, focussing on the use of stavudine and didanosine in particular.

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Patient population

Individuals included in this study were from the EuroSIDA study; a prospective, observational study of patients with HIV-1 in 92 centres across Europe, and Argentina and Israel [1]. The centres provided data for consecutive patients seen in outpatient clinics from May 1994 until a predefined number of patients, a number based both on the size of the clinic and the availability of staff to provide the necessary information, were enrolled from each centre. To be eligible for inclusion, patients needed to have a prebooked clinic appointment and be aged over 16 years. The EuroSIDA I cohort was the first 3116 patients enrolled. Subsequently, six further cohorts of patients have been enrolled, with patients in the seventh cohort (n = 2337) recruited between November 2005 and May 2006. For cohorts I–III, patients were required to have a CD4 cell count measurement of less than 500 cells/μl recorded in the previous 4 months at enrolment. This requirement was removed for cohorts IV–VII.

Information from patient notes is provided on a standardized data collection form at baseline and every 6 months thereafter. Follow-up is until Spring 2006. At every follow-up visit, information on all measured CD4 cell counts and viral loads, and all start and stop dates for each antiretroviral agent received are recorded. Other laboratory indices are also routinely measured. A rigorous quality assurance programme has been established [1]. Informed consent and ethics committee approval were obtained in every participating centre according to national guidelines.

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Ascertainment of pancreatitis

During yearly visits to all sites participating in the EuroSIDA study by clinical monitors, all reported cases of pancreatitis [either by indicating (see follow-up forms at that pancreatitis occurred in the previous 12 months, or if given as a cause of death] are monitored and the source verified. In addition, a monitoring of 10% randomly selected patients in the entire EuroSIDA cohort ensures that the risk of missing any clinical pancreatitis events is minimal. The verification of the pancreatitis event during monitoring is conducted within the same year of the event, unless delayed event reporting occurs.

Pancreatitis events were classified into three categories: definitive acute pancreatitis, definitive chronic pancreatitis and presumptive (acute or chronic) pancreatitis. Definitive acute pancreatitis cases occurred when either definitive acute pancreatitis was diagnosed by the treating physician (in the medical record or during monitoring), or all three of the following occurred: (i) one or more characteristic symptoms or characteristic signs of pancreatitis; (ii) raised enzymes [lipase > 1.5 × upper limit of normal (ULN) or amylase > 1.5 × ULN or pancreas-type isoamylase > 1.5 × ULN]; (iii) at least one imaging investigation (e.g. description of computed tomography/ultrasound) suggested pancreatitis. Definitive chronic pancreatitis was defined as the occurrence of one of the following events; (i) the event was described as definitive chronic (or relapsing acute) pancreatitis by the treating physician (in the medical record or during monitoring); (ii) there were known previous episodes of pancreatitis (often related to alcohol); (iii) there was calcification on pancreas imaging investigations suggesting chronic pancreatitis; (iv) repeated episodes of ‘relapsing acute pancreatitis’ were reported. Presumptive acute or chronic pancreatitis was defined if two of the three following had occurred: (i) one or more characteristic symptoms or characteristic signs of pancreatitis; (ii) raised enzymes (lipase > 1.5 × ULN or amylase > 1.5 × ULN or pancreas-type isoamylase > 1.5 × ULN); (iii) at least one imaging investigation, suggesting pancreatitis according to a radiologist or clinician. Patients were also defined as having presumptive acute or chronic pancreatitis if either the patient had serum amylase greater than four times the ULN and other aetiology was excluded (i.e. salivary gland disease, gut perforation or infarction) or if it was impossible to obtain definitive source documentation. Any reported cases of pancreatitis not meeting the criteria listed above were not included.

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Statistical methods

The EuroSIDA follow-up form first included a question asking whether pancreatitis had occurred in the previous 12 months on the visit 16 form, which took place in Spring–Summer 2002. To minimize potential biases from including events that occurred before recruitment, no individual was included before the date of their EuroSIDA entry visit. Individuals were thus followed from the date of visit 16 minus 12 months or their first visit date, whichever occurred later. This date was arbitrarily defined as the baseline. Follow-up ceased on either the date of a pancreatic event, or on the date that the last follow-up visit form was completed, whichever happened sooner. Patients with no prospective follow-up according to these criteria were excluded. Only the first pancreatic event for each individual that occurred during the study period was considered.

Poisson regression models were used to investigate which factors were associated with pancreatitis. Cumulative ART use was stratified into five categories according to the NRTI included in the regimen: didanosine plus stavudine, stavudine without didanosine (but could be with other NRTI), didanosine without stavudine (but could be with other NRTI), other ART regimens, and no ART. Person-years of follow-up accumulated within each of the possible ART combinations, and patients could move between groups and accumulate follow-up in each group, depending on the antiretroviral drugs they had used. The primary analysis was an ‘on treatment’ analysis; patients were assigned to the category of ART according to treatment at entry (minus 6 months) in to the analysis, and were assigned to this regimen until discontinuation plus 6 months. After the 6-month lag time, the follow-up time was re-assigned according to the patients' switch. Therefore, pancreatic events that occurred when an individual was receiving a particular NRTI combination, or that occurred within 6 months after cessation of the NRTI combination, were considered to be associated with the NRTI combination in question. Those factors significantly associated with the outcome at the 10% level in a univariable model were included in a multivariable model, although ART use was always included.

We carried out a sensitivity analysis in which individuals were categorized according to whether they had ever received: ART including stavudine with didanosine or not, ART including didanosine without stavudine or not, ART including stavudine without didanosine or not, and other ART or not. These variables were time-updated. We also repeated the main analysis, excluding presumptive pancreatic events, and investigated the effects of fitting CD4 cell counts and viral loads as time-updated variables rather than as fixed-time variables at baseline.

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Patient population

A total of 9678 patients were included and were followed for a median (interquartile range; IQR) of 4.3 years (2.2, 4.9 years). The median (IQR) date of entry into the study was July 2001 (May 2001, September 2003). Compared with the 4584 EuroSIDA study participants not included in this present analysis (as they did not have recorded follow-up during the study period of interest), those included were more likely to be women (22.3% of those excluded versus 25.5% of those included; P < 0.0001) and to have a heterosexual risk of HIV transmission (23.6 versus 28.9%; P < 0.0001).

Most patients were men (7211; 74.5%), of white ethnicity (8435; 88.2%) and with a homosexual/bisexual risk of HIV transmission (3993; 41.3%; Table 1). The median (IQR) age at study entry was 39.8 years (34.5, 46.8). At baseline the median (IQR) CD4 cell count and HIV-RNA viral load were 415 (266, 593; n = 9606) cells/μl and 141 (49, 3800; n = 9181) copies/ml, respectively. Most patients (77.8%) were receiving ART at study entry minus 6 months. Of the 3300 individuals who had ever been exposed to didanosine without stavudine, the median (IQR) length of exposure was 1.1 years (0.5, 2.2), of the 4548 individuals ever exposed to stavudine without didanosine this was 2.3 years (1.2, 3.4), and of the 2165 individuals ever exposed to didanosine and stavudine concurrently this was 1.2 years (0.5, 2.2). When considering the current treatment received at study entry minus 6 months, 916 (9.5%) were receiving ART including stavudine and didanosine, 2371 (24.5%) ART including stavudine without didanosine, 847 (8.8%) ART including didanosine without stavudine, and 3400 (35.1%) were receiving other ART regimens.

Table 1

Table 1

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Pancreatic events

There were 43 cases of pancreatitis (nine presumptive) in the follow-up period. Twenty-six of these patients underwent imaging investigation. Three patients had signs of one or more gallstones, of which one was thought to have gallstone-induced pancreatitis. The characteristics of these 43 patients at the time of study entry are shown in Table 1. In comparison with the whole study population, these patients had lower baseline CD4 cell counts (P = 0.0003 Mann–Whitney U test), higher baseline viral loads (P = 0.01 Mann–Whitney U test), and were more likely to have a previous AIDS diagnosis (P = 0.06 chi-squared test) and to be of white ethnicity (P = 0.04 chi-squared test). Table 2 shows the characteristics of each individual who experienced pancreatitis at the time of the pancreatic event. Forty patients had received NRTI at some point before experiencing pancreatitis, and all but seven patients had received NRTI in the 6-month period before diagnosis. There was a range of CD4 cell counts at the time of diagnosis from 1 cell/μl to 902 cells/μl, with a median of 280 cells/μl.

Table 2

Table 2

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Incidence of pancreatitis

We observed 43 cases of pancreatitis during 33 742 person-years of follow-up, which led to an incidence rate of 1.27 per 1000 person-years of follow-up [95% confidence interval (CI) 0.89, 1.66]. A Kaplan–Meier plot of the probability of pancreatitis is shown in Figure 1. When calculating the rates of pancreatitis according to the length of exposure to ART (Table 3), we found that this rate was 1.24 per 1000 person-years among those with no exposure to ART including stavudine and didanosine, 1.73 per 1000 person-years among those who had been exposed to ART including stavudine and didanosine for less than 2 years, and 0.78 per 1000 person-years among those with more than 2 years' exposure. Similarly, we found comparable rates of pancreatitis regardless of the duration of exposure to ART including didanosine without stavudine, ART including stavudine without didanosine, and other ART regimens.

Fig. 1

Fig. 1

Table 3

Table 3

In a univariable Poisson regression analysis (Table 4), there was evidence that lower CD4 cell counts, higher HIV-RNA viral loads, hepatitis C virus positivity, and coming from the central region of Europe were all associated with an increased risk of pancreatitis. In a multivariable analysis, however, only the CD4 cell count was associated with pancreatitis. For every 100 cells/μl higher CD4 cell count, the risk of pancreatitis decreased by 22% [rate ratio (RR) 0.78; 95% CI 0.66, 0.93; P = 0.002]. For those with a baseline CD4 cell count below the median value of 415 cells/μl, the incidence of pancreatitis was 1.93 per 1000 person-years of follow-up (1.26, 2.59), compared with 0.64 events per 1000 person-years (0.32, 1.15) for those above the median value. There was also some evidence that a higher viral load was associated with an increased risk of pancreatitis, although this was not significant at the 5% level (RR 1.10 per 1 log copies/ml higher; 0.99, 1.21; P = 0.09). There was no evidence that the incidence of pancreatitis increased with later calendar years (RR 0.88 per year later; 95% CI 0.72, 1.09; P = 0.24). There was also no evidence of an association with ART use. Each additional year of exposure to ART regimens containing both didanosine and stavudine was associated with a 4% reduction in the risk of pancreatitis (RR 0.96; 95% CI 0.72, 1.27; P = 0.75). The RR for didanosine without stavudine was 0.92 per year longer exposure (0.72, 1.19; P = 0.58), 0.98 for stavudine without didanosine (0.83, 1.16; P = 0.80) and for other ART was 1.03 (0.94, 1.12; P = 0.58).

Table 4

Table 4

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Sensitivity analyses

The above analysis was repeated using an intent-to-treat approach, as described in the Methods, with a time-updated treatment variable. In a multivariable analysis, again only the CD4 cell count was associated with the occurrence of pancreatitis at the 5% level (RR 0.79; 95% CI 0.66–0.94; P = 0.0004), although there was weak evidence of an association with the viral load (RR 1.09; 95% CI 0.99, 1.21; P = 0.09). Compared with those who had never received an ART regimen containing stavudine and didanosine, those who had done so had a RR of pancreatitis of 0.96 (95% CI 0.48, 1.91; P = 0.90). Those who had received an ART regimen containing didanosine without stavudine had an adjusted RR of 1.07 compared with those who had never done so (95% CI 0.54, 2.16; P = 0.84), those who had ever received an ART regimen containing stavudine without didanosine had a RR of 1.31 (95% CI 0.65, 2.64; P = 0.44), and those who had ever received other ART had an adjusted RR of 1.16 (95% CI 0.40, 3.38; P = 0.78) compared with those who had never received other ART.

When only including definitive acute and chronic cases of pancreatitis, we observed 34 cases in 33 754 person-years of follow-up (incidence rate 1.01 per 1000 person-years; 95% CI 0.67–1.35). Multivariable Poisson regression results were very similar to those presented in Table 4 (data not shown). Fitting CD4 cell counts and viral loads as time-updated variables also led to virtually identical results to those presented in the main analysis (data not shown). When considering the use of didanosine with tenofovir, we found a relative risk of 0.78 for each year's additional exposure, although this was accompanied by a wide confidence interval (95% CI 0.21, 2.92; P = 0.69).

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To date, 13 of the 43 patients diagnosed with pancreatitis have died (Table 2). Twelve months after diagnosis with pancreatitis 26.0% had died (95% CI 12.0%, 39.9%; Kaplan–Meier estimate). For three patients, the cause of death was given as pancreatitis; these deaths occurred 0 months (immediate cause of death: lactic acidosis), 0.4 and 0.8 months (underlying cause of death: septicaemia/invasive bacterial infection) after diagnosis. Other causes of death were: bleeding from oesophageal varicose veins (10.9 months after pancreatitis diagnosis); systemic inflammatory response syndrome and disseminated intravascular coagulation (0.3 months); end-stage liver disease, contributed to by acute cholecystitis, hepatitis B chronic infection and hepatic encephalopathy, with an underlying cause of treatment failure and last taking ART more than 2 years before death (38.8 months); pericarditis fibrosa purulenta. (4.6 months); renal failure (4.6 months); non-Hodgkin's lymphoma (2.5 months); cryptococcosis (10.1 months); non-myocardial infarction and non-stroke cardiovascular disease (44.5 months); and unknown in two cases (7.0 and 9.1 months).

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Studies in various European countries have shown regional differences in the incidence of pancreatitis in the general HIV-negative population. Nonetheless, estimates of the incidence lie in the region of five to 80 cases per 100 000 person-years, which is a two to 30-fold lower incidence than the 1.27 cases per 1000 person-years observed in our study [18–25]. There are several possible explanations for the higher incidence observed in our population. Patients in our study were young (the median age was 39.8 years), and may have higher alcohol consumption rates and be more at risk of hyperlipidaemia than the general population, all of which are risk factors for development of pancreatitis [18,19,26]. Furthermore, HIV infection itself may play a role, with studies reporting an increasing risk associated with more advanced disease progression [26,27]. Other studies considering the rate of pancreatitis among HIV-positive patients have similarly found rates of pancreatitis that are higher than those observed in the general population [10–13,28,29]. The rates of pancreatitis observed in those studies were, however, higher than those observed in the present study. Dutta et al. [29] considered 321 patients seen in the period 1993–1994 and found that 45 (14%) developed pancreatitis. Reisler et al. [12] found a rate of pancreatitis of 0.61 per 100 person-years in the period 1989–1999, and a rate of 0.85 per 100 person-years in the period 1996–2001 [28]. As these studies were carried out in earlier calendar years compared with our present study, possible explanations may be an increase in antiretroviral use in more recent calendar years, and changes over time in the specific antiretroviral drugs used, an issue that is discussed in detail below. Nonetheless, the absolute risk in the EuroSIDA study population is relatively small, and patients are at a low risk of developing pancreatitis.

We found no evidence to support the hypothesis that antiretroviral therapy including a NRTI backbone containing didanosine or stavudine was associated with a higher risk of developing pancreatitis. There was also no evidence that receiving both NRTI in combination was associated with an increased risk. Furthermore, we found no evidence that cumulative exposure to any other antiretroviral regimens was associated with an increased risk of pancreatitis. All of these relative risk estimates were close to one, suggesting that any effect of antiretroviral therapy on the occurrence of pancreatitis is likely to be small. Although we cannot rule out a larger treatment effect because of the small number of events, it is also worth noting that there was extensive follow-up of patients, with a median follow-up of over 4 years.

Other studies have found an association between didanosine or stavudine and an increased risk of pancreatitis [11,12], but this has not been replicated in all studies [10,13]. Those studies, like ours, are restricted by the low incidence of pancreatitis, which means that estimates of the effects of these antiretroviral drugs on incidence are often imprecisely estimated.

We found that the risk of pancreatitis was increased for those with lower CD4 cell counts. There was also evidence of an association with higher viral loads, perhaps suggesting that those with more advanced disease were at greater risk. This finding replicates other studies that found an increased risk of pancreatitis among those with more advanced disease [11,13,26]. Other studies in HIV-positive individuals have found an increased risk of pancreatitis among women [11,13], although this has not been the case for all studies [10]. This finding may be affected by the underlying cause of pancreatitis: it has been reported in HIV-negative populations that women are at an increased risk of gallstone pancreatitis and men are at an increased risk of alcoholic pancreatitis, even after adjusting for alcohol consumption [30,31]. We found no sex difference in our study, although the underlying cause of pancreatitis was not studied. In HIV-positive populations, sex differences can often be explained by lower body mass indices in women, but we found no association between pancreatitis and body mass index. A further risk factor for pancreatitis among HIV-positive individuals previously observed is the use of hydroxyurea, particularly in combination with didanosine [13,15]. Unfortunately, insufficient numbers of patients in the EuroSIDA study group have received hydroxyurea during the study period, and so we were unable to investigate this issue further.

All data within the EuroSIDA study are subject to quality control and source verification. In response to concerns about pancreatitis, EuroSIDA started to collect these events prospectively from 2001 onwards. Therefore, we are unable to comment on the rate of pancreatitis in earlier calendar years. It is possible that a number of events occurred before this date and that we have underestimated the incidence. On the other hand, as concerns about the relationship between pancreatitis and the concomitant use of didanosine and stavudine have occurred more recently, one might expect any reporting bias to result in an increased incidence with increasing calendar time, as clinicians became more aware of the potential problem. Between the years 2001 and 2006, we found no association between the incidence of pancreatitis and calendar time. Furthermore, an annual monitoring of 10% of randomly selected patients throughout the entire study period should ensure that the risk of missing any clinical pancreatitis events is minimal. A further potential limitation of our study is that it was conducted in an era when didanosine use was likely to be less widespread than in earlier years. Therefore, much of the cumulative exposure to didanosine without stavudine and to didanosine with stavudine is likely to be previous, rather than current, exposure. We wished to perform a prospective study, however, to ensure that information on pancreatic events was accurately collected, and also so that no cases were missed, which may have happened in a retrospective study. We also have no information on alcohol consumption and limited lipid data, both of which are associated with pancreatitis. In addition, we have considered clinical pancreatitis, and thus subclinical disease has not been considered.

To conclude, we observed a low incidence of pancreatitis within the EuroSIDA study, and there was no evidence to suggest an increase over time in the years 2001–2006. Furthermore, there was no association between specific antiretroviral drugs, or combinations of antiretroviral drugs, associated with the development of pancreatitis.

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The multicentre study group on EuroSIDA (national coordinators in parenthesis):

Argentina: (M. Losso) A. Duran, Hospital J.M. Ramos Mejia, Buenos Aires.

Austria: (N. Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna.

Belarus: (I. Karpov) A. Vassilenko, Belarus State Medical University, Minsk.

Belgium: (N. Clumeck) S. De Wit, B. Poll, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp.

Czech Republic: (L. Machala) H. Rozsypal, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen.

Denmark: (J. Nielsen) J. Lundgren, T. Benfield, O. Kirk, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A.-B.E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense.

Estonia: (K. Zilmer) West-Tallinn Central Hospital, Tallinn.

France: (C. Katlama) Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard, Hôpital Necker-Enfants Malades, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; T. Saint-Marc, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice; F. Dabis, Unité INSERM, Bordeaux.

Germany: M. Dietrich, C. Manegold, Bernhard-Nocht-Institut for Tropical Medicine, Hamburg; J. van Lunzen, H.-J. Stellbrink, Eppendorf Medizinische Kernklinik, Hamburg; S. Staszewski, M. Bickel, J.W. Goethe University Hospital, Frankfurt; F.-D. Goebel, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne; J. Rockstroh, Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover.

Greece: (J. Kosmidis) P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital, Athens; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital, Athens.

Hungary: (D. Banhegyi) Szent László Hospital, Budapest.

Ireland: (F. Mulcahy) St James's Hospital, Dublin.

Israel: (I. Yust) D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa: Z. Sthoeger, Kaplan Hospital, Rehovot; S. Maayan, Hadassah University Hospital, Jerusalem.

Italy: (A. Chiesi) Istituto Superiore di Sanità, Rome; R. Esposito, I. Mazeu, Università Modena, Modena; C. Arici, Ospedale Riuniti, Bergamo; R. Pristera, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S. Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, Presidio Ospedaliero AD. Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; A.L. Ridolfo, S. Corvasce, Osp. L. Sacco, Milan; A. D'Arminio Monforte, Clinica Malattie Ifettive e Tropicali, Milan.

Latvia: (L. Viksna) Infectology Centre of Latvia, Riga.

Lithuania: (S. Chaplinskas) Lithuanian AIDS Centre, Vilnius.

Luxembourg: (R. Hemmer) T. Staub, Centre Hospitalier, Luxembourg.

Netherlands: (P. Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam.

Norway: (J. Bruun) A. Maeland, V. Ormaasen, Ullevål Hospital, Oslo.

Poland: (B. Knysz) J. Gasiorowski, Medical University, Wroclaw; A. Horban, Centrum Diagnostyki i Terapii AIDS, Warsaw; D. Prokopowicz, A. Wiercinska-Drapalo, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk.

Portugal: (F. Antunes) E. Valadas, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon.

Romania: (D. Duiculescu) Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucarest; A. Streinu-Cercel, Institute of Infectious Diseases, Bucarest.

Russia: E. Vinogradova, St Petersburg AIDS Centre; A. Rakhmanova, Medical Academy Botkin Hospital, St Petersburg.

Serbia and Montenegro: (D. Jevtovic) The Institute for Infectious and Tropical Diseases, Belgrade.

Slovakia: (M. Mokráš) D. Staneková, Dérer Hospital, Bratislava.

Spain: (J. González-Lahoz) M. Sánchez-Conde, T. García-Benayas, L. Martin-Carbonero, V. Soriano, Hospital Carlos III, Madrid; B. Clotet, A. Jou, J. Conejero, C. Tural, Hospital Germans Trias i Pujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona.

Sweden: (A. Blaxhult) Karolinska University Hospital, Solna; A. Karlsson, Karolinska University Hospital, Stockholm; P. Pehrson, Karolinska University Hospital, Huddinge.

Switzerland: (B. Ledergerber) R. Weber, University Hospital, Zürich; P. Francioli, A. Telenti, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, V. Soravia-Dunand, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern.

Ukraine: (E. Kravchenko) N. Chentsova, Kyiv Centre for AIDS, Kyiv.

United Kingdom: (S. Barton) St Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus); A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; R. Brettle, Western General Hospital, Edinburgh.

Virology Group: B. Clotet (Central Coordinators) plus ad hoc virologists from participating sites in the EuroSIDA study.

Steering Committee: F. Antunes, B. Clotet, D. Duiculescu, J. Gatell, B. Gazzard, A. Horban, A. Karlsson, C. Katlama, B. Ledergerber (Chair), A. D'Arminio Montforte, A. Phillips, A. Rakhmanova, P. Reiss (Vice-Chair), J. Rockstroh.

Coordinating Centre Staff: J. Lundgren (project leader), I. Gjørup, O. Kirk, A. Mocroft, N. Friis-Møller, A. Cozzi-Lepri, W. Bannister, M. Ellefson, A. Borch, D. Podlekareva, C. Holkmann Olsen, J. Kjær.

Sponsorship: The European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Framework (QLK2-2000-00773) and the 6th Framework (LSHP-CT-2006-018632) programmes were the primary sponsors of the study. Unrestricted grants were also provided by Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck and Co., Tibotec and Boehringer-Ingelheim. The participation of centres from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.

Conflicts of interest: None.

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antiretroviral therapy; didanosine; pancreatitis; stavudine

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