Lancet. 2014 Jul 19;384(9939):241-8.

Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.
Smith CJ1, Ryom L2, Weber R3, Morlat P4, Pradier C5, Reiss P6, Kowalska JD7, de Wit S8, Law M9, el Sadr W10, Kirk O2, Friis-Moller N11, Monforte Ad12, Phillips AN13, Sabin CA13, Lundgren JD2; D:A:D Study Group.
Collaborators (728)Powderly B, Shortman N, Moecklinghoff C, Reilly G, Franquet X, Ryom L, Sabin CA, Kamara D, Smith C, Phillips A, Mocroft A, Tverland J, Mansfeld M, Nielsen J, Raben D, Lundgren JD, Salbøl Brandt R, Rickenbach M, Fanti I, Krum E, Hillebregt M, Geffard S, Sundström A, Delforge M, Fontas E, Torres F, McManus H, Wright S, Kjær J, Sjøl A, Meidahl P, Helweg-Larsen J, Schmidt Iversen J, Ryom L, Mocroft A, Kirk O, Reiss P, Ross M, Fux CA, Morlat P, Moranne O, Kesselring AM, Kamara DA, Smith C, Lundgren JD, Smith C, Ryom L, Phillips A, Weber R, Morlat P, Pradier C, Reiss P, Friis-Møller N, Kowalska J, Lundgren JD, Sabin C, Law M, d'Arminio Monforte A, Dabis F, Bruyand M, Reiss P, Smith C, Kamara DA, Bower M, Fätkenheuer G, Donald A, Grulich A, Ryom L, Lundgren JD, Reiss P, Zaheri S, Hillebregt M, Gras L, Prins JM, Kuijpers TW, Scherpbier HJ, Boer K, van der Meer JT, Wit FW, Godfried MH, Reiss P, van der Poll T, Nellen FJ, Lange JM, Geerlings SE, van Vugt M, Vrouenraets SM, Pajkrt D, van der Valk M, Schreij G, Lowe S, Oude Lashof A, Pronk MJ, Bravenboer B, van der Ende ME, de Vries-Sluijs TE, Schurink CA, van der Feltz M, Nouwen JL, Gelinck LB, Verbon A, Rijnders BJ, Slobbe L, Hartwig NG, Driessen GJ, Branger J, Kauffmann RH, Schippers EF, Groeneveld PH, Alleman MA, Bouwhuis JW, ten Kate RW, Soetekouw R, Kroon FP, van den Broek PJ, van Dissel JT, Arend SM, van Nieuwkoop C, de Boer MG, Jolink H, den Hollander JG, Pogany K, van Twillert G, Kortmann W, Vriesendorp R, Leyten EM, ten Napel CH, Kootstra GJ, Brinkman K, Blok WL, Frissen PH, Schouten WE, van den Berk GE, Juttmann JR, van Kasteren ME, Brouwer AE, Veenstra J, Lettinga KD, Mulder JW, van Gorp EC, Smit PM, Weijer S, van Eeden A, Verhagen DW, Sprenger HG, Doedens R, Scholvinck EH, van Assen S, Stek CJ, Koopmans PP, de Groot R, Keuter M, van der Ven AJ, ter Hofstede HJ, van der Flier M, Brouwer AM, Dofferhoff AS, Hoepelman AI, Mudrikova T, Schneider MM, Jaspers CA, Ellerbroek PM, Peters EJ, Maarschalk-Ellerbroek LJ, Oosterheert JJ, Arends JE, Wassenberg MW, van der Hilst JC, Danner SA, van Agtmael MA, de Vocht J, Perenboom RM, Claessen FA, Bierman WF, de Jong EV, bij de Vaate EA, Geelen SP, Wolfs TF, Richter C, van der Berg JP, Gisolf EH, van den Berge M, Stegeman A, van Houte DP, Polée MB, van Vonderen MG, Winkel C, Duits AJ, Dabis F, Bruyand M, Chêne G, Dabis F, Lawson-Ayayi S, Thiébaut R, Bonnal F, Bonnet F, Bernard N, Caunègre L, Cazanave C, Ceccaldi J, Chambon D, Chossat I, Dauchy FA, De Witte S, Dupon M, Duffau P, Dutronc H, Farbos S, Gaborieau V, Gemain MC, Gerard Y, Greib C, Hessamfar M, Lacoste D, Lataste P, Lafarie S, Lazaro E, Malvy D, Meraud JP, Mercié P, Monlun E, Morlat P, Neau D, Ochoa A, Pellegrin JL, Pistone T, Ragnaud JM, Receveur MC, Tchamgoué S, Vandenhende MA, Viallard JF, Moreau JF, Pellegrin I, Fleury H, Lafon ME, Masquelier B, Trimoulet P, Breilh D, Haramburu F, Miremont-Salamé G, Blaizeau MJ, Decoin M, Delaune J, Delveaux S, D'Ivernois C, Hanapier C, Leleux O, Uwamaliya-Nziyumvira B, Sicard X, Geffard S, Palmer G, Touchard D, Bonnet F, Dupon M, Mercié P, Morlat P, Pellegrin JL, Ragnaud JM, Dabis F, Law M, Petoumenos K, McManus H, Wright S, Bendall C, Moore R, Edwards S, Hoy J, Watson K, Roth N, Nicholson J, Bloch M, Franic T, Baker D, Vale R, Carr A, Cooper D, Chuah J, Ngieng M, Nolan D, Skett J, Calvo G, Torres F, Mateu S, Domingo P, Sambeat MA, Gatell J, Del Cacho E, Cadafalch J, Fuster M, Codina C, Sirera G, Vaqué A, De Wit S, Clumeck N, Delforge M, Necsoi C, Clumeck N, De Wit S, Gennotte AF, Gerard M, Kabeya K, Konopnicki D, Libois A, Martin C, Payen MC, Semaille P, Van Laethem Y, Neaton J, Bartsch G, El-Sadr WM, Krum E, Thompson G, Wentworth D, Luskin-Hawk R, Telzak E, El-Sadr WM, Abrams DI, Cohn D, Markowitz N, Arduino R, Mushatt D, Friedland G, Perez G, Tedaldi E, Fisher E, Gordin F, Crane LR, Sampson J, Baxter J, Lundgren J, Kirk O, Mocroft A, Cozzi-Lepri A, Grint D, Podlekareva D, Kjær J, Peters L, Reekie J, Kowalska J, Tverland J, Fischer AH, Nielsen J, Losso M, Elias C, Vetter N, Zangerle R, Karpov I, Vassilenko A, Mitsura VM, Suetnov O, Clumeck N, De Wit S, Delforge M, Colebunders R, Vandekerckhove L, Hadziosmanovic V, Kostov K, Begovac J, Machala L, Jilich D, Sedlacek D, Nielsen J, Kronborg G, Benfield T, Larsen M, Gerstoft J, Katzenstein T, Hansen AB, Skinhøj P, Pedersen C, Ostergaard L, Zilmer K, Smidt J, Ristola M, Katlama C, Viard JP, Girard PM, Livrozet JM, Vanhems P, Pradier C, Dabis F, Neau D, Rockstroh J, Schmidt R, van Lunzen J, Degen O, Stellbrink HJ, Staszewski S, Bickel M, Fätkenheuer G, Kosmidis J, Gargalianos P, Xylomenos G, Perdios J, Panos G, Filandras A, Karabatsaki E, Sambatakou H, Banhegyi D, Mulcahy F, Yust I, Turner D, Burke M, Pollack S, Hassoun G, Maayan S, Vella S, Esposito R, Mazeu I, Mussini C, Arici C, Pristera R, Mazzotta F, Gabbuti A, Vullo V, Lichtner M, Chirianni A, Montesarchio E, Gargiulo M, Antonucci G, Testa A, Narciso P, Vlassi C, Zaccarelli M, Lazzarin A, Castagna A, Gianotti N, Galli M, Ridolfo A, d'Arminio Monforte A, Rozentale B, Zeltina I, Chaplinskas S, Hemmer R, Staub T, Reiss P, Ormaasen V, Maeland A, Bruun J, Knysz B, Gasiorowski J, Horban A, Bakowska E, Grzeszczuk A, Flisiak R, Boron-Kaczmarska A, Pynka M, Parczewski M, Beniowski M, Mularska E, Trocha H, Jablonowska E, Malolepsza E, Wojcik K, Antunes F, Doroana M, Caldeira L, Mansinho K, Maltez F, Duiculescu D, Rakhmanova A, Zakharova N, Buzunova S, Jevtovic D, MokrᚠM, Staneková D, Tomazic J, González-Lahoz J, Soriano V, Labarga P, Medrano J, Moreno S, Rodriguez JM, Clotet B, Jou A, Paredes R, Tural C, Puig J, Bravo I, Gatell JM, Miró JM, Domingo P, Gutierrez M, Mateo G, Sambeat MA, Karlsson A, Flamholc L, Ledergerber B, Weber R, Francioli P, Cavassini M, Hirschel B, Boffi E, Furrer H, Battegay M, Elzi L, Kravchenko E, Chentsova N, Frolov V, Kutsyna G, Servitskiy S, Krasnov M, Barton S, Johnson AM, Mercey D, Phillips A, Johnson MA, Mocroft A, Murphy M, Weber J, Scullard G, Fisher M, Leen C, Morfeldt L, Thulin G, Sundström A, Åkerlund B, Koppel K, Karlsson A, Flamholc L, Håkangård C, Moroni M, Antinori A, Carosi G, Cauda R, Chiodo F, d'Arminio Monforte A, Di Perri G, Galli M, Ghinelli F, Iardino R, Ippolito G, Lazzarin A, Mazzotta F, Panebianco R, Pastore G, Perno CF, d'Arminio Monforte A, Ammassari A, Antinori A, Balotta C, Bonfanti P, Capobianchi MR, Castagna A, Ceccherini- Silberstein F, Cozzi-Lepri A, d'Arminio Monforte A, De Luca A, Gervasoni C, Girardi E, Lo Caputo S, Maggiolo F, Murri R, Mussini C, Puoti M, Torti C, Cozzi-Lepri A, Fanti I, Formenti T, Montroni M, Giacometti A, Costantini A, Riva A, Tirelli U, Martellotta F, Pastore G, Ladisa N, Suter F, Maggiolo F, Chiodo F, Verucchi G, Fiorini C, Carosi G, Cristini G, Torti C, Minardi C, Bertelli D, Quirino T, Abeli C, Manconi PE, Piano P, Vecchiet J, Farenga M, Carnevale G, Lorenzotti S, Ghinelli F, Sighinolfi L, Leoncini F, Mazzotta F, Pozzi M, Lo Caputo S, Pagano G, Cassola G, Viscoli G, Alessandrini A, Piscopo R, Mazzarello G, Soscia F, Tacconi L, Orani A, Rossotto R, Tommasi D, Congedo P, Chiodera A, Castelli P, Galli M, Lazzarin A, Rizzardini G, Schlacht I, d'Arminio Monforte A, Ridolfo AL, Foschi A, Castagna A, Salpietro S, Merli S, Melzi S, Moioli MC, Cicconi P, Formenti T, Esposito R, Mussini C, Gori A, Abrescia N, Chirianni A, Izzo CM, De Marco M, Viglietti R, Manzillo E, Ferrari C, Pizzaferri P, Baldelli F, Camanni G, Magnani G, Ursitti MA, Arlotti M, Ortolani P, Cauda R, Andreoni M, Antinori A, Antonucci G, Narciso P, Tozzi V, Vullo V, De Luca A, Zaccarelli M, Acinapura R, De Longis P, Trotta MP, Lichtner M, Carletti F, Mura MS, Madeddu G, Caramello P, Di Perri G, Orofino GC, Raise E, Ebo F, Pellizzer G, Buonfrate D, Pradier C, Fontas E, Caissotti C, Dellamonica P, Bernard E, Cua E, De Salvador-Guillouet F, Durant J, Ferrando S, Mondain-Miton V, Naqvi A, Perbost I, Prouvost-Keller B, Pillet S, Pugliese P, Rahelinirina V, Roger PM, Dollet K, Barth J, Battegay M, Bernasconi E, Böni J, Bucher HC, Burton-Jeangros C, Calmy A, Cavassini M, Cellerai C, Dubs R, Egger M, Elzi L, Fehr J, Flepp M, Francioli P, Furrer H, Fux CA, Gorgievski M, Günthard H, Hasse B, Hirsch HH, Hirschel B, Hösli I, Kahlert C, Kaiser L, Keiser O, Kind C, Klimkait T, Kovari H, Ledergerber B, Martinetti G, Martinez de Tejada B, Müller N, Nadal D, Pantaleo G, Rauch A, Regenass S, Rickenbach M, Rudin C, Schmid P, Schultze D, Schöni-Affolter F, Schüpbach J, Speck R, Taffé P, Telenti A, Trkola A, Vernazza P, von Wyl V, Weber R, Yerly S.

Author information 1Research Department of Infection and Population Health, University College London, London, UK. Electronic address: c.smith@ucl.ac.uk.2CHIP, Department of Infectious Diseases (2100), Rigshospitalet, University of Copenhagen, Denmark.3Division of Infectious Diseases, University Hospital Zurich, University of Zurich, Zurich Switzerland.4Service de Medecine Intern et Maladies Infectieuses, CHU de Bordeaux, Universite Bordeaux Segalen, Bordeaux, France.5Department of Public Health, Nice University Hospital, Nice, France.6Academic Medical Center, University of Amsterdam, and Stichting HIV Monitoring, Netherlands.7Department of Adult's Infectious Diseases, Medical University of Warsaw, Poland.8Department of Infectious Diseases, St Pierre University Hospital, Brussels, Belgium.9The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.10Mailman School of Public Health, Columbia University, New York, USA.11Department of Infectious Diseases, Odense University Hospital, Denmark.12Department of Health Sciences, San Paolo University Hospital, Milan, Italy.13Research Department of Infection and Population Health, University College London, London, UK.

Abstract
BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011.

METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression.

FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11).

INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement.

FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.


Comment in

Antiretroviral therapy: stubborn limitations persist. [Lancet. 2014]

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