Published by Oxford University Press on behalf of the International Epidemiological Association ß The Author 2008; all rights reserved. Advance Access publication 17 September 2008
International Journal of Epidemiology 2009;38:1202–1206 doi:10.1093/ije/dyn192
COHORT PROFILE
Cohort Profile: The Danish HIV Cohort Study Niels Obel,1* Frederik N Engsig,1 Line D Rasmussen,2 Mette V Larsen,3 Lars H Omland1 and Henrik T Sørensen4,5
Accepted
18 August 2008
How did the study come about? Shortly after AIDS was recognized in USA, the first cases were diagnosed in Denmark.1,2 Today Denmark has a population of 5.3 million citizens and the prevalence of HIV infection in the adult population is estimated at 0.07%.3,4 Denmark’s HIV epidemic is characterized by the ‘western world pattern’ in which the main transmission routes in the 1980s were between men who had sex with men (MSM), with later spread to heterosexual groups. Since 1995 mortality in the Danish HIV population has fallen drastically as a consequence of highly active antiretroviral therapy (HAART), followed by an increase in HIV prevalence.5 HIV incidence has been rather stable. Denmark’s tax-funded health care system provides treatment, including antiretroviral therapy, free-of-charge to all HIV-positive residents. The treatment of HIV-infected patients occurs only in eight specialized medical centres. Due to the nature of the epidemic and the challenges of modern antiretroviral treatment (e.g. HAART effectiveness, drug toxicity, drug resistance and comorbidity) the need for a tool to monitor HIV became evident. The aims of the Danish HIV Cohort Study (DHCS) were (i) to create a population-based nationwide database of HIV patients for scientific projects, (ii) to monitor the spread and demographics of the HIV epidemic in Denmark, (iii) to monitor and compare the effects of treatment strategies in Danish HIV treatment centres 1
Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark. 2 Depertment of Infectious Diseases, Odense University Hospital, Odense, Denmark. 3 Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark. 4 Department of Clinical Epidemiology, Aarhus University Hospital, Denmark. 5 Department of Epidemiology, Boston University, Boston, MA, USA. * Corresponding author. Department of Infectious Diseases, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail:
[email protected]
and (iv) to monitor the effect of HAART on a national level. Denmark provides an optimal environment for cohort studies: (i) all Danish citizens can be tracked in the health care system and national registries through use of a unique civil registration number, (ii) treatment of HIV patients is restricted to eight medical centres and (iii) Denmark has several national registries that store information on patient demographics and characteristics of hospital admissions. The DHCS is an open, prospective, populationbased cohort, initiated in 1998 as a collaborative effort by Denmark’s eight HIV treatment centres. DHCS has a director and a steering committee, which includes a representative from each centre.
Who set up DHSC and why, and how was it funded? The cohort was set up by Niels Obel and the steering committee of The Danish HIV Cohort Study to estimate the numbers of HIV infected patients under treatment in Denmark and to monitor the effects of HAART. It was initially financed by a grant from the Danish AIDS Foundation, a non-profit organization.
What does the cohort cover? The cohort covers all HIV infected individuals followed at Danish HIV treatment clinics.
What were the original research topics? The original research topics of DHCS were to monitor the numbers of HIV patients treated in Denmark and effects of HAART on morbidity and mortality.
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Who is in the sample? DHCS includes all HIV-infected individuals, aged 16 years or older at time of HIV diagnosis, seen in one of the eight Danish HIV centres after 31 December 1994. All patients who died or emigrated after this date are included in the cohort. HIV patients are identified from hospital records and electronic laboratory reports of CD4 counts and HIV-RNA viral loads. As these tests are conducted on all HIV patients in the centres as part of initial screening, the risk that a patient is missed in DHCS is negligible. The demographics of the cohort are presented in Table 1. At the present time DHCS includes 4720 individuals, of whom 3543 are males. MSM was reported as the route of
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infection in 2129 cases and 1778 persons were infected heterosexually. The majority of patients are treated in the two major HIV centres located in Copenhagen (Rigshospitalet and Hvidovre Hospital). The cohort has 31 029 person-years of follow up. The study is approved by the Danish Data Agency.
How often have they been followed up? Since the introduction of HAART, HIV patients have been followed on an outpatient basis at intended intervals of 12 weeks. Data extracted from patient
Table 1 Baseline characteristics of patients in DHCS by collaborating clinical centrea No. of patients Male sex
Total 4720 (100)
RH 1569 (33b)
HV 1774 (38b)
SKS 546 (12b)
O 417 (9b)
Other 414 (9b)
3543 (75)
1303 (83)
1326 (75)
374 (68)
279 (67)
261 (63)
Race Caucasian
3730 (79)
1337 (85)
1438 (81)
390 (71)
280 (67)
285 (69)
Black
658 (14)
138 (9)
211 (12)
114 (21)
105 (25)
90 (22)
Asian
190 (4)
41 (3)
81 (5)
21 (4)
16 (4)
31 (7)
Inuit
47 (1)
15 (1)
14 (1)
9 (2)
5 (1)
4 (1)
Other/unknown
95 (2)
38 (2)
30 (2)
12 (2)
11 (3)
4 (1)
Homosexual sex
2129 (45)
922 (59)
780 (44)
213 (39)
117 (28)
97 (23)
Heterosexual sex
1778 (38)
425 (27)
568 (32)
274 (50)
259 (62)
252 (61)
522 (11)
110 (7)
326 (18)
28 (5)
23 (6)
35 (8)
291 (6)
112 (7)
100 (6)
31 (6)
18 (4)
30 (7)
34 (28–42)
34 (28–42)
34 (28–41)
33 (27–42)
35 (28–43)
34 (28–42)
Route of infection
Injection drug use Other/unknown Age at HIV diagnosis, median years (IQR) Diagnosed with HIV before 1995
1980 (42)
720 (46)
812 (46)
224 (41)
149 (36)
75 (18)
Exposed to HAART
3428 (73)
1168 (74)
1253 (71)
390 (71)
299 (72)
318 (77)
39 (33–46)
39 (33–48)
39 (33–46)
39 (32–46)
39 (33–48)
38 (32–45)
Age at start of HAART, median years (IQR) Time from HIV diagnosis to HAART, median years (IQR)
2.6 (0.2–7.4) 2.8 (0.2–8.9) 3.4 (0.2–8.0)
2.0 (0.1–7.0) 1.3 (0.2–5.6) 0.6 (0.1–3.8)
CD4þ cell count at start of HAART, median cells/ml (IQR)c
190 (80–290) 190 (73–300) 194 (80–280) 198 (90 -300) 190 (90–290) 170 (72–294)
HIV load at start of HAART, median log copies/ml (IQR)c
4.9 (4.2–5.4) 4.9 (4.3–5.3) 4.9 (4.2–6.0)
4.9 (4.3–5.5) 4.8 (4.1–5.3) 4.7 (3.9–5.3)
Treatment-naı¨ve patients at start of HAART
2307 (67)
770 (66)
824 (66)
257 (66)
215 (72)
241 (76)
AIDS-defining event before start of HAART
758 (22)
249 (21)
290 (23)
87 (22)
63 (21)
69 (22)
Data are number (%) of patients, unless otherwise indicated. Percentages may not always equal 100% because of rounding errors. a RH, Copenhagen University Hospital, Rigshospitalet; HV, Copenhagen University Hospital, Hvidovre Hospital; SKS: Aarhus University Hospital, Skejby; O: Odense University Hospital; Other: Aalborg Hospital, Kolding Hospital, Herning Hospital, Helsingør Hospital. b Percentage of total number of patients in DHCS. c Last measurement before start of HAART. If no prior measurement was available, the first measurement up to 30 days after start of therapy was used.
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files and electronic reports are reported to the DHCS on a yearly basis (Table 2). The Danish Civil Registration System makes it possible to track deaths and emigration occurring in the cohort.
What has been measured? The data profile of DHCS is decided by its steering committee. A common form is used to standardize data collection from each of the eight centres. The data is keyed into the computer-based data management system using serial numbers to protect confidentiality and patient privacy. The cohort database includes the following baseline information: date of birth, gender, route of infection, race, place of birth, treatment centre, date of first consultation in the centre, dates of most recent HIV-1 negative and positive tests, first HIV-2 test, date of immi- and emigration, height and weight. Cohort data also include date and classification of the AIDSdefining disease, history of antiretroviral treatment, genotyping, participation in clinical studies, date of death (classified according to CoDe after 2005), diagnosis dates of diabetes and myocardial infarction, treatment for diabetes, blood pressure, date of lipoatrophy, smoking status, alcohol consumption, blood pressure, and, for females, number of births. Laboratory data include CD4 cell counts, HIV-RNA levels, cholesterol levels, triglyceride levels, and serology for cytomegalovirus, toxoplasmosis, and hepatitis B and C. Gender, date of birth and death are confirmed yearly using the Danish Civil Registration System. DHCS data managers generate lists of potential errors (death before HIV-positive diagnosis, initiation of antiretroviral treatment before HIV diagnosis, etc.) on a yearly basis, thereby ensuring continuous data quality improvement.
What is attrition like? Thus far, 1075 patients have died and 238 have emigrated. Of the 238 patients who emigrated, 43 had contact with one of our eight HIV centres more than 3 months subsequent to their emigration date. As HAART is provided in only the eight specialized HIV centers, data on this parameter is complete in DHCS. However, 67 patients who are not registered as having died or emigrated have had no contact with any of the centers since January 1, 2005. As all deaths and emigrations for Danish citizens are registered in the Danish Civil Registration System, follow up concerning these parameters is complete.
in Denmark.4 We found a stable incidence of HIV diagnoses and a decrease in mortality starting in 1995. Two studies have compared the risk of death in HIV-infected patients with that in the background population.5–7 One study yielded an estimate of 63 years as the median survival age for male patients diagnosed at age 25 who are not co-infected with hepatitis C (HCV).5 The survival age is markedly higher than found in the mid 1990s, but still lower than that observed in the background population.5 We found no impact of race on the effect of HAART.8 A study by Lohse et al.9 showed the strong impact of early suppression of viral load on HAART’s long-term effect. In several studies we found a declining incidence of antiretroviral resistance among Danish patients.10–12 In contrast to chronic hepatitis B, which had only a minor impact on overall survival, HCV co-infection was found to substantially increase the risk of death in HIV-infected patients and to eliminate the beneficial effect of HAART.13,14 Several researchers have proposed that increased mortality among HIV/HCV co-infected patients is closely related to socioeconomic factors. Our study of mortality in siblings confirmed this, showing a substantially increased risk of death among siblings of HIV/HCV co-infected patients.15 The excess death rate was explained mainly by substance abuse and other unnatural causes of death.16 Because antiretroviral drugs are associated with a number of metabolic changes, such as insulin resistance and increased cholesterol and triglycerides levels,17,18 it has been hypothesized that HAART may increase the risk of myocardial infarction. We found that the risk of myocardial infarction increased substantially following HAART initiation (adjusted relative risk 2.12), but did not further increase in the first 8 years of therapy with HAART.19 Table 2 Enrolments and deaths in the DHCS Enrollments 1980
Deaths NA
1995
265
248
1996
227
163
1997
233
86
1998
199
62
1999
244
79
2000
225
50
2001
272
68
2002
228
59
2003
204
74
2004
253
78
2005
194
64
Before 1995
What has it found?
2006
196
44
In 2005 DHCS data were used to describe the demographics and development of the HIV epidemic
Total
4720
1075
NA, not applicable.
COHORT PROFILE: DANISH HIV COHORT STUDY
As well, post-myocardial infarction mortality in HIVinfected patients was as expected given the additive risks of myocardial infarction and HIV.20 DHCS has been involved in several international cohort studies.21–24
What are the main strengths and weaknesses? DHCS, established at the same time that HAART became available, has a nationwide, population-based design with complete long-term follow up. Use of the unique 10-digit civil registration number assigned to all Danes allows us to avoid multiple registrations and to extract data from: (i) the Danish National Hospital Registry, with data on all hospital admission and discharge diagnoses since 1977 and all hospital outpatient visits since 1995, (ii) the Danish Civil Registration System, which contains data on immigration, emigration and death, (iii) the Danish National Registry of Deaths, which registers causes of death for all Danish citizens and (iv) the Danish Cancer Registry, which documents all cancer diagnoses in Denmark. These registries also provide information on comorbidities, such as myocardial infarction, as well as date and cause of death. Furthermore, they allow us to identify population controls matched on age, gender and place of residence and to extract data on their health status. Information on siblings of HIV-infected patients and matched population controls can also be extracted. Electronic access to laboratory data allows complete follow up on the clinical course of illness. The main weaknesses of DHCS are the rather small number of patients in the cohort and the lack of information on patients diagnosed with HIV who died before January 1, 1995. The cohort is thus most useful for studies of frequently occurring endpoints.
Can I get hold of the data? Where can I find out more? DHCS is administered according to Danish law. Its steering committee provides oversight and the study director is responsible for day-to-day management. DHCS participates in international collaborations at the discretion of the steering committee (COHERE, CHAVI). Potential collaborators are invited to contact the study director, Niels Obel (e-mail:
[email protected]).
Odense University Hospital, Preben and Anna Simonsen’s Foundation, the Foundation of the Danish Association of Pharmacists and the Clinical Institute of the University of Southern Denmark for financial support. Centres in the DHCS are as follows: Departments of Infectious Diseases at Copenhagen University Hospitals, Rigshospitalet (J Gerstoft, N Obel) and Hvidovre (G Kronborg), Odense University Hospital (C Pedersen), Aarhus University Hospitals, Skejby (CS Larsen) and Aalborg (G Pedersen), Herning Hospital (AL Laursen), Helsingør Hospital (L Nielsen) and Kolding Hospital (J Jensen). Conflict of interest: None declared.
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Acknowledgements We thank the staff of our clinical departments for their continuous support and enthusiasm. We also thank the Danish AIDS Foundation, Rigshospitalet,
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