Liver-related Death Among HIV/hepatitis C Virus-co-infected Individuals

Implications for the Era of Directly Acting Antivirals

Daniel Grint; Lars Peters; Juergen K. Rockstroh; Aza Rakmanova; Tatiana Trofimova; Karine Lacombe; Igor Karpov; Massimo Galli; Pere Domingo; Ole Kirk; Jens D. Lundgren; Amanda Mocroft

Disclosures

AIDS. 2015;29(10):1205-1215.

Abstract and Introduction

Abstract

Background: Potent, less toxic, directly acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) infection promise to improve HCV cure rates among HIV/HCV-co-infected individuals. However, the costs of treatment will necessitate prioritization of those at greatest risk of liver-related death (LRD) for therapy. This study aims to provide guidance on who should be prioritized for DAA treatment.

Methods: Three thousand, nine hundred and forty-one HCV antibody-positive PSHREG and FIB-4 are names not acronyms (EuroSIDA) patients with follow-up after 1 January 2000 were included, with causes of death classified using Coding causes of Death in HIV (CoDe) methodology. Crude death rates, competing-risks Cox proportional-hazards models and cumulative incidence functions were used to describe factors associated with LRD.

Results: LRD accounted for 145 of 670 (21.6%) deaths in the study population. LRD rates peaked in those aged 35–45 years, and occurred almost exclusively in those with at least F2 fibrosis at baseline. In adjusted Cox models, risk factors for LRD included F4 or F2/F3 fibrosis [sub-distribution hazard ratio (sHR) 6.3, 95% confidence interval (CI) 4.1–9.6; and sHR 2.5, 95% CI 1.5–4.2 vs. F0/F1, respectively), CD4⁺ cell count (sHR 0.83, 95% CI 0.73–0.95 per doubling) and hepatitis B surface antigen-positive (sHR 2.2, 95% CI 1.3–3.5 vs. hepatitis B surface antigen-negative). The 5-year probability of LRD was low in those with F0/F1 fibrosis (sHR 2.2%, 95% CI 1.7–2.9), but substantial in those with F2/F3 and F4 fibrosis (sHR 10.3%, 95% CI 7.6–13.5; and sHR 14.0%, 95% CI 10.3–18.3, respectively).

Conclusion: Treatment with DAAs should be prioritized for those with at least F2 fibrosis. Early initiation of cART with the aim of avoiding low CD4⁺ cell counts should be considered essential to decrease the risk of LRD and the need for HCV treatment.

Introduction

The substantial declines in HIV-related mortality, as a consequence of the introduction of combination antiretroviral therapy (cART), have seen liver-related death (LRD) assume increasing relative importance among HIV-positive individuals.^[1,2] Although progression of liver disease is common with hepatitis C virus (HCV) infection and known to be accelerated in the presence of HIV,^[3] LRD is often associated with older age as complications of HCV-related liver disease usually take decades to develop.^[4] During this period, HCV-co-infected individuals have many competing risks of death, such as mortality associated with injecting drug use, AIDS, cardiovascular disease, malignancies, bacterial infections, violent death and renal disease.^[2]

While the uptake of treatment for HCV has so far been low among HIV/HCV-co-infected individuals in Europe, in particular, among injecting drug users (IDUs), this is partially explained by the costs of treatment, potential contraindication to interferon-based treatments, anticipated poor treatment adherence and low treatment efficacy of pegylated interferon and ribavirin.^[5] However, with the recent approval of less toxic, oral, directly acting antivirals (DAAs) for HCV, fewer co-infected individuals will have contraindications to HCV treatment, while treatment outcomes will be significantly improved and approach the HCV cure rate of above 90% seen for HCV-monoinfected individuals.^[6,7]

The potential benefits of curative treatment with new DAAs are numerous, including reductions in fibrosis progression, LRD and extra-hepatic manifestations, along with limiting ongoing transmission.^[8] However, regardless of the advances in HCV treatment, the approximate costs of [Euro sign]50 000–90 000 per treatment for the currently approved DAAs and the expectation that new oral combination regimens will be more expensive still^[9] will, in many countries, necessitate the prioritization of individuals for treatment. Therefore, a better understanding of the spectrum of causes of death among HIV/HCV-co-infected individuals, factors that affect progression to LRD and potential competing risks is essential in determining who to prioritize for treatment of HCV infection.

The aims of this study were to describe causes of death among HIV/HCV-co-infected individuals naive to interferon-based treatment, to identify factors associated with LRD and to provide guidance on who should be prioritized for treatment of HCV infection with DAAs.

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Lippincott Williams & Wilkins

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics.
Median (IQR) %		All (N=3941)	Causes of death				P value*
Median (IQR) %		All (N=3941)	LRD (N=145)	AIDS (N=162)	Non-LRD non-AIDS (N=233)	Unknown causes (N=130)	P value*
Age		37 (31–43)	39 (35–43)	36 (31–42)	39 (34–46)	40 (35–46)	0.0004
Baseline date		Oct 2005 (Jul 2002–Jul 2008)	Dec 2001 (Jan 2000–Aug 2005)	Jan 2005 (Feb 2001–Jan 2008)	Mar 2003 (Jan 2000–Aug 2005)	Jun 2004 (Jan 2000–Jul 2006)	<0.0001
Male		2677 (67.9)	103 (71.0)	117 (72.2)	180 (77.3)	95 (73.1)	0.5209
White		3687 (93.6)	136 (93.8)	158 (97.5)	221 (94.8)	112 (86.2)	0.0008
Region of EuroSIDA	South	1005 (25.5)	42 (29.0)	29 (17.9)	46 (19.7)	17 (13.1)	<0.0001
	West	551 (14.0)	28 (19.3)	12 (7.4)	25 (10.7)	34 (26.2)
	North	495 (12.6)	37 (25.5)	24 (14.8)	74 (31.8)	34 (26.2)
	East central	562 (14.3)	13 (9.0)	10 (6.2)	29 (12.4)	12 (9.2)
	East	1223 (31.0)	23 (15.9)	80 (49.4)	54 (23.2)	31 (23.8)
	Argentina	105 (2.7)	2 (1.4)	7 (4.3)	5 (2.1)	2 (1.5)
HIV transmission route	MSM	344 (8.7)	8 (5.5)	9 (5.6)	17 (7.3)	7 (5.4)	0.4108
	IDU	2760 (70.0)	113 (77.9)	122 (75.3)	188 (80.7)	106 (81.5)
	Heterosexual	603 (15.3)	12 (8.3)	23 (14.2)	19 (8.2)	11 (8.5)
	Other	234 (5.9)	12 (8.3)	8 (4.9)	9 (3.9)	6 (4.6)
HCV-RNA status	Negative	409 (10.4)	10 (6.9)	13 (8.0)	32 (13.7)	15 (11.5)	<0.0001
	Positive	1831 (46.5)	87 (60.0)	55 (34.0)	120 (51.5)	67 (51.5)
	Unknown	1701 (43.2)	48 (33.1)	94 (58.0)	81 (34.8)	48 (36.9)
Minimum duration of HCV infection	Years	2.8 (0.7–6.0)	4.1 (2.2–7.0)	2.1 (0.2–5.2)	4.0 (1.5–6.7)	3.9 (0.8–7.5)	<0.0001
HCV genotype	G1	959 (24.3)	47 (32.4)	25 (15.4)	52 (22.3)	34 (26.2)	0.0020
	G2	52 (1.3)	2 (1.4)	4 (2.5)	3 (1.3)	4 (3.1)
	G3	558 (14.2)	22 (15.2)	16 (9.9)	45 (19.3)	20 (15.4)
	G4	268 (6.8)	8 (5.5)	4 (2.5)	9 (3.9)	9 (6.9)
	Unknown	2104 (53.4)	66 (45.5)	113 (69.8)	124 (53.2)	63 (48.5)
HBsAg status	Negative	3338 (84.7)	116 (80.0)	136 (84.0)	202 (86.7)	104 (80.0)	0.0021
	Positive	281 (7.1)	23 (15.9)	17 (10.5)	18 (7.7)	8 (6.2)
	Unknown	322 (8.2)	6 (4.1)	9 (5.6)	13 (5.6)	18 (13.8)
CD4⁺ cell count	Cells/μl	382 (239–563)	216 (100–393)	200 (76–357)	303 (153–515)	277 (140–485)	<0.0001
CD4⁺ nadir	Cells/ml	166 (72–288)	96 (36–200)	101 (28–205)	115 (52–220)	113 (50–211)	0.2917
HIV-RNA	<400 copies/ml	2048 (59.0)	60 (44.8)	27 (24.1)	105 (49.1)	51 (45.5)	0.0002
Liver fibrosis	F0/F1	2543 (64.5)	33 (22.8)	66 (40.7)	116 (49.8)	52 (40.0)	<0.0001
	F2/F3	211 (5.4)	17 (11.7)	7 (4.3)	11 (4.7)	10 (7.7)
	F4	322 (8.2)	38 (26.2)	13 (8.0)	19 (8.2)	15 (11.5)
	Unknown	865 (21.9)	57 (39.3)	76 (46.9)	87 (37.3)	53 (40.8)

Alcohol abuse is omitted from this table as it was added to the EuroSIDA CRF in 2010. During follow-up, 60.5% of the study population have information on alcohol abuse with 13.4% reporting current alcohol abuse. HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; IDU, injecting drug user; LRD, liver-related death.
*P value from Kruskal–Wallis or chi-square test comparing the individual causes of death.

Table 2. Crude death rates.
Patient strata	Causes of death
Patient strata	Overall (N=670)	Liver-related (N=145)	AIDS (N=162)	Non-LRD/non-AIDS (N=233)	Unknown (N=130)
Age (years)
<35	31.8 (26.6–37.1)	4.0 (2.1–5.9)	11.7 (8.5–14.9)	11.5 (8.3–14.7)	4.7 (2.6–6.7)
35–45	44.0 (39.1–49.0)	12.0 (9.4–14.7)	11.0 (8.5–13.5)	13.6 (10.8–16.4)	7.5 (5.4–9.5)
45–55	40.6 (34.7–46.5)	9.9 (6.9–12.8)	6.7 (4.2–9.1)	14.2 (10.7–17.7)	9.9 (6.9–12.8)
>55	75.6 (58.3–92.8)	6.7 (1.4–12.0)	12.2 (5.0–19.4)	36.7 (24.4–49.0)	20.0 (10.9–29.2)
Region of EuroSIDA
South	30.9 (25.7–36.0)	9.7 (6.8–12.6)	6.7 (4.3–9.1)	10.6 (7.6–13.7)	3.9 (2.1–5.8)
West Central	40.9 (33.0–48.7)	11.6 (7.3–15.8)	5.0 (2.2–7.7)	10.3 (6.3–14.3)	14.0 (9.4–18.7)
North	81.0 (69.3–92.7)	17.7 (12.1–23.4)	11.5 (6.9–16.1)	35.5 (27.5–43.4)	16.3 (10.9–21.7)
East Central	22.3 (16.9–27.7)	4.5 (2.1–7.0)	3.5 (1.3–5.6)	10.1 (6.4–13.8)	4.2 (1.8–6.5)
East	48.1 (41.4–54.8)	5.9 (3.5–8.3)	20.5 (16.0–24.9)	13.8 (10.2–17.5)	7.9 (5.1–10.7)
Argentina	34.4 (17.8–50.9)	4.3 (0.0–10.2)	15.0 (4.0–26.1)	10.7 (1.4–20.1)	4.3 (0.0–10.2)
HCV-RNA status^a
HCV-RNA-negative	32.5 (25.3–39.6)	5.6 (2.5–8.6)	6.4 (3.2–9.6)	13.7 (9.0–18.4)	6.8 (3.5–10.2)
HCV-RNA-positive	39.1 (35.1–43.0)	10.1 (8.1–12.2)	6.7 (5.0–8.3)	14.3 (11.9–16.7)	8.0 (6.2–9.8)
Unknown	51.8 (45.3–58.3)	8.5 (5.8–11.2)	19.1 (15.0–23.1)	15.2 (11.7–18.8)	9.0 (6.2–11.7)
HBV status^a
HBsAg-negative	40.3 (37.0–43.5)	8.3 (6.8–9.8)	9.6 (8.0–11.2)	14.8 (12.8–16.8)	7.6 (6.2–9.1)
HBsAg-positive	61.3 (47.3–75.3)	21.3 (12.9–29.7)	16.9 (9.3–24.4)	15.1 (8.0–22.2)	8.0 (2.8–13.2)
Unknown	38.1 (24.9–51.2)	4.9 (0.1–9.7)	8.6 (2.3–14.9)	8.6 (2.3–14.9)	16.0 (7.4–24.6)
Transmission risk group
MSM	32.7 (22.9–42.6)	6.4 (2.0–10.8)	7.2 (2.5–11.9)	13.6 (7.2–20.0)	5.6 (1.5–9.7)
IDU	45.5 (41.7–49.3)	9.7 (7.9–11.5)	10.5 (8.6–12.4)	16.2 (13.9–18.5)	9.1 (7.4–10.9)
Other	31.0 (25.0–37.0)	7.4 (4.5–10.4)	9.6 (6.3–13.0)	8.7 (5.5–11.9)	5.3 (2.8–7.8)
CD4⁺ cell count^a
<200	145.5 (130.7–160.3)	37.1 (29.1–45.0)	51.7 (42.4–61.0)	37.5 (29.6–45.5)	19.2 (13.5–25.0)
200–350	41.9 (35.3–48.4)	8.9 (5.8–12.0)	6.7 (4.0–9.4)	15.6 (11.6–19.7)	10.6 (7.3–14.0)
350–500	21.1 (16.5–25.7)	4.0 (2.0–6.0)	2.6 (1.0–4.3)	10.3 (7.1–13.5)	4.2 (2.2–6.3)
>500	16.1 (13.1–19.2)	2.2 (1.0–3.3)	1.1 (0.3–1.9)	7.8 (5.6–9.9)	5.1 (3.4–6.9)
HIV-RNA^a
<500	27.7 (24.6–30.7)	5.3 (4.0–6.7)	4.3 (3.1–5.5)	12.2 (10.2–14.3)	5.9 (4.4–7.3)
500–1000	46.3 (24.8–67.7)	8.2 (0.0–17.4)	19.1 (5.1–33.0)	10.9 (0.3–21.5)	8.2 (0.0–17.4)
>1000	74.3 (65.8–82.8)	20.3 (15.8–24.9)	19.8 (15.3–24.3)	20.9 (16.3–25.5)	13.3 (9.6–17.0)
Alcohol abuse^a
None	26.9 (21.2–32.6)	2.9 (1.0–4.8)	8.7 (5.5–12.0)	9.1 (5.7–12.4)	6.2 (3.4–8.9)
Current	110.3 (79.9–140.7)	36.8 (18.5–55.0)	34.3 (16.7–52.0)	27.0 (11.2–42.7)	12.3 (1.6–22.9)
Unknown	43.0 (39.5–46.6)	9.6 (7.9–11.3)	9.6 (7.9–11.3)	15.4 (13.3–17.6)	8.4 (6.8–10.0)
Liver fibrosis^a
F0/F1	18.7 (16.0–21.5)	1.2 (0.5–1.9)	5.6 (4.1–7.1)	7.9 (6.1–9.7)	4.0 (2.7–5.3)
F2/F3	27.2 (15.1–39.2)	10.0 (2.6–17.4)	5.7 (0.1–11.3)	8.6 (1.7–15.4)	2.9 (0.0–6.8)
F4	103.8 (86.6–121.0)	42.4 (31.0–53.7)	14.1 (7.5–20.8)	30.7 (21.0–40.5)	16.6 (9.4–23.8)
Unknown	73.6 (66.2–81.1)	16.0 (12.5–19.6)	18.6 (14.7–22.4)	24.3 (19.9–28.6)	14.8 (11.3–18.2)

All rates and 95% confidence intervals per 1000 PYFU. HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IDU, injecting drug user; LRD, liver-related death; PYFU, person-years of follow-up.
^aTime-updated variables.

Authors and Disclosures

Daniel Grint^a, Lars Peters^b, Juergen K. Rockstroh^c, Aza Rakmanova^d, Tatiana Trofimova^e, Karine Lacombe^f, Igor Karpov^g, Massimo Galli^h, Pere Domingoi, Ole Kirk^b, Jens D. Lundgren^b AND Amanda Mocroft^a

^aUCL, London, UK, ^bCHIP, Department of Infectious Diseases and Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, ^cDepartment of Medicine I, University of Bonn, Bonn, Germany, ^dBotkin Hospital of Infectious Diseases, St Petersburg, ^eNovgorod Centre for AIDS, Novgorod, Russia, ^fHospital Saint Antoine, Paris, France, ^gBelarus State Medical University, Minsk, Belarus, ^hSacco hospital, Milan, Italy, and ⁱHospital de Sant Pau, Barcelona, Spain.

Correspondence to
Daniel Grint, HIV Epidemiology & Biostatistics Group, Research Department of Infection and Population Health, UCL – Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: +44 20 7794 0500 ext. 34684; e-mail: d.grint@ucl.ac.uk

Author contributions
D.G. led the study with supporting contributions from L.P., J.D.L. and A.M. D.G. performed the statistical analyses. D.G., J.D.L., L.P., O.K. and A.M. designed the study and D.G. drafted the manuscript. All co-authors contributed to redrafting and refinement of the manuscript. A.M. supervised the study.
EuroSIDA study group: The multicentre study group, EuroSIDA (national coordinators in parenthesis). Argentina: (M. Losso), M. Kundro, Hospital JM 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; D. Paduto, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck), S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; E. Florence, 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, N.F. Møller, Odense University Hospital, Odense; L. Ostergaard, Skejby Hospital, Aarhus, U.B. Dragsted, Roskilde Hospital, Roskilde; L.N. Nielsen, Hillerod Hospital, Hillerod. 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, Hôtel-Dieu, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice; F. Dabis, D. Neau, Unité INSERM, Bordeaux, C. Duvivier, Hôpital Necker-Enfants Malades, Paris. 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; C. Stefan, J.W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Georgia: (N. Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi. Greece: (J. Kosmidis), P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; H. Sambatakou, Ippokration General Hospital, Athens. Hungary: (D Banhegyi), Szent Lásló Hospital, Budapest. Iceland: (M. Gottfredsson), Landspitali University Hospital, Reykjavik. Ireland: (F. Mulcahy), St. James' Hospital, Dublin. Israel: (I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; E. Shahar, G. Hassoun, Rambam Medical Center, Haifa; H. Elinav, M. Haouzi, Hadassah University Hospital, Jerusalem; Z.M. Sthoeger, AIDS Center (Neve Or), Jerusalem. Italy: (A. D'Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; 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; M. Zaccarelli, A. Antinori, R. Acinapura, G. D'Offizi, 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. Latvia: (B. Rozentale), Infectology Centre of Latvia, Riga. Lithuania: V Uzdaviniene, Lithuanian AIDS Centre, Vilnius. Luxembourg: (T. Staub), R. Hemmer, 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, M. Inglot, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; A. Grzeszczuk, R. Flisiak, Medical University, Bialystok; M. Parczewski, M. Pynka, K. Maciejewska, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; T. Smiatacz, Medical University, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; I. Mozer-Lisewska, Poznan University of Medical Sciences, Poznan. Portugal: (M. Doroana), L. Caldeira, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. Romania: (R. Radoi), C. Oprea, Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucarest. Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; A. Rakhmanova, St Petersburg AIDS Centre, St Peterburg; T. Trofimora, Novgorod Centre for AIDS, Novgorod, I. Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E. Kuzovatova, Nizhny Novgorod Scientific and Research Institute, Nizhny Novogrod. Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: A. Shunnar, D Staneková, Dérer Hospital, Bratislava. Slovenia: (J. Tomazic), University Clinical Centre Ljubljana, Ljubljana. Spain: S. Moreno, J. M. Rodriguez, 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 Universitari de Barcelona, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona; J.M. Laporte, Hospital Universitario de Alava, Vitoria-Gasteiz. Sweden: (A. Blaxhult), Venhaelsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö, A. Thalme, A. Sonnerborg, Karolinska University Hospital, Stockholm. Switzerland: (B. Ledergerber), R. Weber, University Hospital, Zürich; M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; A. Calmy, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel; P. Schmid, Kantonsspital, St. Gallen. Ukraine: (E. Kravchenko), N. Chentsova, Kiev Centre for AIDS, Kiev; V. Frolov, G. Kutsyna, I. Baskakov, Luhansk State Medical University, Luhansk; S. Servitskiy, Odessa Region AIDS Center, Odessa; A. Kuznetsova, Kharkov State Medical University, Kharkov; G. Kyselyova, Crimean Republican AIDS Centre, Simferopol. United Kingdom: (B. Gazzard), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, E. Simons, S. Edwards, Mortimer Market Centre, London; A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); C. Orkin, Royal London 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.
The following centres have previously contributed data to EuroSIDA: Bernhard Nocht Institut für Tropenmedizin, Hamburg, Germany; 1st I.K.A Hospital of Athens, Athens, Greece; Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy; Ospedale Cotugno, III Divisione Malattie Infettive, Napoli, Italy; Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain.
EuroSIDA Steering Committee: J. Gatell, B. Gazzard, A. Horban, I. Karpov, B. Ledergerber, M. Losso, A. d'Arminio Monforte, C. Pedersen, A. Rakhmanova, M. Ristola, A. Phillips, P. Reiss, J. Lundgren, J. Rockstroh, S. De Wit
Coordinating Centre Staff: D. Podlekareva, L. Peters, J.E. Nielsen, C. Matthews, A.H. Fischer, A. Bojesen, D. Raben, D. Kristensen, K. Grønborg Laut, J.F. Larsen. Statistical Centre Staff: A. Mocroft, A. Phillips, A. Cozzi-Lepri, D. Grint, L. Shepherd, A. Schultze.

Conflicts of interest
O.K. has received honorarium, consultancy and/or lecture fees from Abbott, Gilead, GSK, Janssen, Merck, Tibotec and Viiv. A.M. has received honorarium, consultancy or guest speaker fees from Pfizer, Merck, Gilead, BI and BMS. J.R. has received consultancy or lecture fees from Bionor, BMS, BI, GSK, ViiV, Abbott, Gilead, Pfizer, Merck, Tibotec and Janssen. All other authors have no conflicts of interest to report for the present study.