Figure 2 shows the risk of death stratified by date of starting cART (<2002 and ≥2002). After adjustment, the risk of all cause, AIDS and non-AIDS-related death in both groups reflected the same trend as observed in the main analyses; however, due to the low number of events it was not possible to further investigate trends for non-AIDS cause-specific deaths.
When time on cART was fitted as continuous variable from 2 years of exposure onwards there was a 5% decrease in the risk of all-cause death [incidence rate ratio (IRR) 0.95, 95% CI 0.92–0.97, P < 0.0001] and 14% decrease in the risk of AIDS-related death (IRR 0.86, 95% CI 0.81–0.91, P < 0.0001) per one additional year on cART, and a borderline significant decrease in the risk of non-AIDS death (IRR 0.97, 95% CI 0.95–1.00, P = 0.06) (Table 3). These findings were consistent while investigating trends from 4 years of exposure onwards.
Of note the risk of non-AIDS death was significantly lower in the first 2 years on cART, which was mostly driven by LR-death and CVD-death (Table 2), and not observed in patients starting cART in 2002 and onwards (Fig. 2).
Sensitivity analyses investigated the incidence rate of cause-specific deaths with cumulative exposure to cART restricting the group of patients to those recruited to the study after 1 January 2002, a period in which there was increasing representation of patients from Eastern Europe. In a separate set of analyses, we also explored the effect of excluding injecting drug users and patients who started cART before enrolment to EuroSIDA. We obtained consistent results, namely no discernable increase in death rate beyond 2–3.99 years of exposure to treatment, although due to lower number of endpoints the confidence intervals were wider (data not shown).
The main finding of our study was that there was no evidence of an increase in the risk of any non-AIDS-related death with prolonged exposure to cART. This is, to our knowledge, the first study to look into the association of non-AIDS cause-specific deaths with duration of time actually spent on cART and with a long-term perspective of exposure to treatment. The results are reassuring that so far prolonged use of cART does not appear to be leading to increased risk of death due to some previously identified cumulative effect, or a drug effect whereby there is a long induction period before disease appears.
Our analyses confirm the prolonged benefit of cART, with a 5% decrease in the overall risk of death per additional year on treatment, which was mostly attributed to a decrease in the risk of AIDS-related death. When non-AIDS cause-specific deaths were investigated contrasting trends for different death causes were evident. For example the risk of LR-death, violent, and unknown death decreased with additional year spent on cART, whereas there was a trend towards an increase in NADM-death. The lower risk of violent death with increasing time on cART could relate to stabilized heath conditions, lifestyle changes or improvement in socio-economic status of those patients who retain in care . The risk of dying from unknown cause also decreased over time spent on cART suggesting that patients sustaining on long-term treatment have more predictable outcomes.
The increase in NADM-death rate may reflect aging of the HIV population, as the effect was no longer present after adjustment for time updated age (data not shown), or improvement in cancer screening. However, it becomes clear that merging all non-AIDS-related deaths in one group might not be sufficient to detect any negative effects of exposure to cART.
Palella et al. reported longer time spent on cART to be associated with increased risk of death due to non-AIDS cause. This study did not investigate more specific non-AIDS causes and the majority of patients were less than 4 years on cART. The Antiretroviral Therapy Cohort Collaboration investigated detailed cause-specific mortality rates according to time since first started cART and found the increases in crude incidence rate of NADM-death, CVD-death and LR-death with time since starting cART that was no longer significant after baseline characteristics were taken into account . However, only a limited number of factors were available for model adjustment.
The observed lower risk of non-AIDS death in the first 2 years after treatment initiation, that was more pronounced in patients who started cART prior to 2002 might be due to several potential confounding factors that we were not able to control, for example misclassification of some non-AIDS deaths as AIDS-related deaths or underestimation in the rate of death due to loss to follow-up . However, the rate of loss to follow-up in EuroSIDA is below 5 per 100 PYFU and stable over the study period .
A clear advantage of our analyses is that the underlying cause of death is determined based on a standardized method of assessing the causal link between a disease or condition and death, namely the Coding Causes of Death in HIV (CoDe) . In addition a separate algorithm classifying all deaths without known causes as either unknown AIDS or unknown non-AIDS-related has been applied, which allowed inclusion of all deaths into our analyses .
EuroSIDA is an observational cohort and therefore there may remain unknown or unmeasured confounders that we were unable to adjust for. For example, we were not able to control for the effect of alcohol use or treatment for comorbidities, as this information was not routinely collected through the whole follow-up period. We were also not able to adjust for calendar year of follow-up as it was highly correlated with time on cART, but repeating the models stratifying by year of starting treatment receiving similar results as for the main models. Furthermore, the effect of particular antiretroviral drugs or drug classes on cause-specific mortality could not be investigated due to the low number of events available after such stratification. Since mechanisms of toxicities for individual antiretroviral drugs or drug classes vary significantly they may well have different effects on morbidity and mortality [9,23–25].
As follow-up data accumulate, such analyses will be possible enabling clinicians to compose cART regimens with the optimal risk-benefit ratio for the individual patients .
It is important to underline that proper managing of conventional risk factors will prevent developing both cART and non-cART-related metabolic diseases leading to further decrease in many cause-specific deaths [26,27].
It is clear that death due to accumulating treatment toxicities is a very uncommon event. Although we did not find the risk of any specific non-AIDS-related death to increase with prolonged exposure to cART, we cannot at present exclude that such risk may exists for specific sub-groups of patients or individual antiretroviral drugs.
Life-long cART is the current standard of care for HIV-positive people and the duration of cART exposure is only going to continue to increase with improved patient survival. The growing burden of non-AIDS-related comorbidities highlights the need to collect information with longitudinal perspective and continues to focus on the underlying causes of death. Clearly a greater understanding of any risks associated with long-term exposure to cART is needed and future research should further investigate the incidence rates of cause-specific death as an important tool in monitoring overall treatment benefit and long-term drug safety.
Design of the study: J.D.K., A.M., J.R., O.K., J.L., A.P.
Analysis design: J.K., J.R., A.P., O.K., J.L., A.M.
Statistical analysis of the data: J.R, A.M.
Contribution to the writing of the paper: J.D.K., J.R., A.M., P.R., B.L., J.G., A.d’A.M., A.P., J.D.L. O.K.
Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94–1637), BIOMED 2 (CT97–2713), the 5th Framework (QLK2–2000–00773), the 6th Framework (LSHP-CT-2006–018632), and the 7th Framework (FP7/2007–2013, EuroCoord n° 260694) programmes. Current support also includes unrestricted grants by Gilead, Pfizer, BMS, and Merck and Co.; the participation of centres from Switzerland was supported by The Swiss National Science Foundation (Grant 108787).
The EuroSIDA Study Group: The multicentre study group on EuroSIDA (national coordinators in parenthesis).
Argentina: (M. Losso), C. Elias, Hospital J.M. Ramos Mejia, Buenos Aires. Austria: (N. Vetter), Pulmologisches Zentrum der Stadt Wien, Vienna; R. Zangerle, Medical University Innsbruck, Innsbruck.Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk, V.M. Mitsura, Gomel State Medical University, Gomel; O. Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck), S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; L. Vandekerckhove, University Ziekenhuis Gent, Gent. Bosnia-Herzegovina: (V. Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: (K. Kostov), Infectious Diseases Hospital, Sofia. Croatia: (J. Begovac), University Hospital of Infectious Diseases, Zagreb.Czech Republic: (L. Machala), D. Jilich, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen. Denmark: (J. Nielsen), G. Kronborg, T. Benfield, M. Larsen, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A.-B.E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense; L. Ostergaard, Skejby Hospital, Aarhus. Estonia: (K. Zilmer), West-Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M. Ristola), Helsinki University Central Hospital, Helsinki. France: (C. Katlama), Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard, Hôpital Necker-Enfants Malades, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; J.M. Livrozet, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l’Archet, Nice; F. Dabis, D. Neau, Unité INSERM, Bordeaux. Germany: (J. Rockstroh), Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover; J. van Lunzen, O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H.J. Stellbrink, IPM Study Center, Hamburg; S. Staszewski, J.W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J. Kosmidis), P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambatakou, Ippokration Genereal Hospital, Athens. Hungary: (D. Banhegyi), Szent Lásló 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; S Maayan, Hadassah University Hospital, Jerusalem. Italy: (S. Vella), Istituto Superiore di Sanità, Rome; R Esposito, I Mazeu, C Mussini, 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, M. Gargiulo, Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli; G. Antonucci, A. Testa, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, A. Castagna, N. Gianotti, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan; A. d’Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan. Latvia: (B. Rozentale), I. Zeltina, 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: (V. Ormaasen), A. Maeland, J. Bruun, Ullevål Hospital, Oslo. Poland: (B. Knysz) J. Gasiorowski, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; A. Grzeszczuk, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, M. Parczewski, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz. Portugal: (F. Antunes), M. Doroana, L. Caldeira, 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. Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; N. Zakharova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M. Mokráš), D Staneková, Dérer Hospital, Bratislava. Slovenia: (J Tomazic), University Clinical Centre Ljubljana, Ljubljana. Spain: (J. González-Lahoz), V. Soriano, P. Labarga, J. Medrano, Hospital Carlos III, Madrid; S. Moreno, Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, 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. Karlsson), Venhaelsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö. Switzerland: (B. Ledergerber), R. Weber, University Hospital, Zürich; P Francioli, M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel. Ukraine: (E. Kravchenko), N. Chentsova, Kiev Centre for AIDS, Kiev; V. Frolov, G. Kutsyna, Luhansk State Medical University; Luhansk; S. Servitskiy, Odessa Region AIDS Center, Odessa; M. Krasnov, Kharkov State Medical University, Kharkov. 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; C. Leen, Western General Hospital, Edinburgh.
Steering committee: J. Gatell, B. Gazzard, A. Horban, B. Ledergerber, M. Losso, J. Lundgren, A. d’Arminio Monforte, C. Pedersen, A. Phillips, A. Rakhmanova, P. Reiss, M. Ristola, J. Rockstroh (Chair), S. De Wit (Vice-Chair).
Coordinating centre staff: J. Lundgren, O. Kirk, A. Mocroft, A. Cozzi-Lepri, D. Grint, M. Ellefson, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska, J. Tverland, A.H. Fischer, J. Nielsen.
Conflicts of interest
There are no conflicts of interest.
1. Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group
2. Martinez E, Milinkovic A, Buira E, de Lazzari E, Leon A, Larrousse M, et al. Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area
. HIV Med
3. Lewden C, May T, Rosenthal E, Burty C, Bonnet F, Costagliola D, et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: The ‘Mortalite 2000 and 2005’ Surveys (ANRS EN19 and Mortavic)
. J Acquir Immune Defic Syndr
4. The Antiretroviral Therapy Cohort Collaboration.Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies.Clin Infect Dis
5. Mocroft A, Brettle R, Kirk O, Blaxhult A, Parkin JM, Antunes F, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study
6. Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe
. J Acquir Immune Defic Syndr
7. Madden E, Lee G, Kotler DP, Wanke C, Lewis CE, Tracy R, et al. Association of antiretroviral therapy with fibrinogen levels in HIV-infection
8. Sankatsing RR, Wit FW, Vogel M, de Groot E, Brinkman K, Rockstroh JK, et al. Increased carotid intima-media thickness in HIV patients treated with protease inhibitors as compared to nonnucleoside reverse transcriptase inhibitors
9. Fontas E, van LF, Sabin CA, Friis-Moller N, Rickenbach M, d’Arminio Monforte A, et al. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles?
. J Infect Dis
10. Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study
. J Infect Dis
11. Strategies for Management of Anti-Retroviral Therapy/INSIGHT; DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients.AIDS
12. Mocroft A, Kirk O, Reiss P, De Wit S, Sedlacek D, Beniowski M, et al. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients
13. Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS
14. Neuhaus J, Angus B, Kowalska JD, La Rosa A, Sampson J, Wentworth D, et al. Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV
15. Reekie J, Gatell J, Yust I, Bakowska E, Rakhmanova A, Losso M, et al. Fatal and nonfatal AIDS and non-AIDS events in HIV-1 positive individuals with high CD4 counts according to viral load strata
16. Mocroft A, Soriano V, Rockstroh J, Reiss P, Kirk O, De Wit S, et al. Is there evidence for an increase in the death rate from liver-related disease in patients with HIV?
17. Kowalska JD, Friis-Moller N, Kirk O, Bannister W, Mocroft A, Sabin C, et al. The Coding Causes of Death in HIV (CoDe) Project: initial results and evaluation of methodology
18. Kowalska JD, Mocroft A, Ledergerber B, Florence E, Ristola M, Begovac J, et al. A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: results from the EuroSIDA study
. HIV Clin Trials
19. Giordano TP, Gifford AL, White AC Jr, Suarez-Almazor ME, Rabeneck L, Hartman C, et al. Retention in care: a challenge to survival with HIV infection
. Clin Infect Dis
20. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study
. J Acquir Immune Defic Syndr
21. Brinkhof MW, Pujades-Rodriguez M, Egger M. Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis
. PLoS One
22. Mocroft A, Kirk O, Aldins P, Chies A, Blaxhult A, Chentsova N, et al. Loss to follow-up in an international, multicentre observational study
. HIV Med
23. Franssen R, Sankatsing RR, Hassink E, Hutten B, Ackermans MT, Brinkman K, et al. Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production
. Arterioscler Thromb Vasc Biol
24. Kristoffersen US, Kofoed K, Kronborg G, Giger AK, Kjaer A, Lebech AM. Reduction in circulating markers of endothelial dysfunction in HIV-infected patients during antiretroviral therapy
. HIV Med
25. Jiang B, Khandelwal AR, Rogers LK, Hebert VY, Kleinedler JJ, Zavecz JH, et al. Antiretrovirals induce endothelial dysfunction via an oxidant-dependent pathway and promote neointimal hyperplasia
. Toxicol Sci
26. Kowalska JD, Kirk O, Mocroft A, Hoj L, Friis-Moller N, Reiss P, et al. Implementing the number needed to harm in clinical practice: risk of myocardial infarction in HIV-1-infected patients treated with abacavir
. HIV Med
27. Petoumenos K, Worm S, Reiss P, De Wit S, d’Arminio Monforte A, Sabin C, et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study(*)
. HIV Med
Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
adverse effects; AIDS; combination antiretroviral therapy; cause of death; HIV; mortality; non-AIDS event