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).
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).
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).
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. considered 321 patients seen in the period 1993–1994 and found that 45 (14%) developed pancreatitis. Reisler et al. 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 . 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 . 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.
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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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; didanosine; pancreatitis; stavudine