Setting
As of 1 January 2007 Denmark had a population of 5,447,084 (Statistics Denmark), with an estimated HIV prevalence of 0.07% among adults [10]. Medical care, including antiretroviral treatment, is tax-paid and provided free-of-charge to all HIV-infected residents of Denmark. Treatment of HIV infection is restricted to eight specialized medical centres, where patients are seen on an outpatient basis at intended intervals of 12 weeks. During our study's follow-up period, national criteria for initiating highly active antiretroviral treatment (HAART) were HIV-related disease, acute HIV infection, pregnancy, CD4 cell count < 300 cells/μl, and, until 2001, plasma HIV-RNA > 100,000 copies/ml.
Study population and data collection
Study subjects
DHCS encompasses all HIV-infected patients treated in the above described Danish HIV clinics since 1 January 1995. Patients are identified from the lists of HIV patients in the eight medical centres, as well as from local data-sources in these centers of patients tested for HIV RNA and/or CD4 cell counts. Because HIV patients undergo tests for HIV-RNA and CD4 count in the centers at least once a year, the risk of DHCS failing to capture HIV-infected patients seen in the centres is negligible. Further the fact that antiretroviral treatment is in Denmark restricted to these eight clinics ensures that very few patients diagnosed with HIV remains unrecognised by DHCS. In Denmark treatment with antiretroviral drugs is restricted to the eight medical centers participating in DHCS. DHCS has been described elsewhere [10]. The date of HIV diagnosis, dates of AIDS-defining diseases and HBV and HCV status, are registered for each patient in DHCS as well as AIDS defining events, antiretroviral treatment, HIV-RNA, CD4 counts etc. The data in DHCS are updated on a yearly basis by research nurses or physicians. HBV and HCV status are reviewed by a trained physician or study nurse at the centres to ensure data quality.
The present study includes all 2,033 DHCS patients who met the following criteria: residence in Denmark at diagnosis (i.e., recorded in the Danish Civil Registration System), diagnosed with HIV after 31 January 1994 and before 1 January 2005, and age 16 years or older at time of diagnosis. Patients positive for the hepatitis-B S antigen on screening are categorised as having chronic HBV in DHCS. Patients positive for HCV serology and/or with positive HCV RNA are categorised as HCV patients.
DNHR
Hospitalisation data for study subjects were obtained from DNHR, which was established in 1977 mainly for administrative and management purposes [11]. This registry includes primary diagnosis as well as co-morbidities [ICD-8 codes until the end of 1993, ICD-10 codes thereafter (ICD-9 has never been used in Denmark)] and procedure codes for patients treated in Danish hospitals. Diagnoses are coded by the hospital physicians at discharge for inpatients and at the initial consultation for the outpatients. Starting on 1 January 1995, the registry was expanded to include outpatients. As the current study is limited to patients diagnosed after 31 December 1994, only ICD-10 codes were relevant. The first date on which a patient was admitted to or seen as an outpatient at a Danish hospital with one of the following diagnosis codes was defined as the DNHR diagnosis date:
HIV: B20.0-B24.9
Chronic hepatitis B: B18.0 or B18.1
Chronic hepatitis C: B18.2
In a sensitivity analysis we expanded these groups to include nonspecific viral hepatitis as follows:
Chronic hepatitis B and nonspecific chronic viral hepatitis: B18.0, B18.1, B18.8, B18.9
Chronic hepatitis C and nonspecific chronic viral hepatitis: B18.2, B18.8, B18.9
Statistical analysis
The numbers of study patients registered with HIV in DNHR and with HBV or HCV coinfection in DNHR and in DHCS were determined. We calculated the completeness (as a measure of sensitivity) of DNHR data as the number of HIV patients recorded with a diagnosis in DNHR divided by the number of patients registered with the diagnosis in DHCS (the reference) [12]. We were not able to compute the predictive value of a HIV diagnosis in the DNHR since we did not have permission from the Danish Data Protection Agency to identify HIV cases recorded only in the DNHR.
Kaplan-Meier analyses were used to construct time-to-event curves. Time was calculated as time elapsed from the DHCS HIV diagnosis date to the registration date of the first HIV diagnosis in DNHR. For patients not registered with HIV in DNHR, time was calculated from the DHCS date of HIV diagnosis to death or to 1 January 2007 (date of last observation in DNHR), whichever came first. [No one was diagnosed with HIV after death in either DNHR or DHCS]. In a few cases the patient was registered with HIV in DNHR before the diagnosis was registered in DHCS, which would give negative time in time to event analysis. In these cases for technically reasons time from registration in DHCS to registration in DNHR was defined to zero.
Cox regression analysis was used to estimate hazard ratios (HR) as a measure of the relative risk of being registered with an HIV diagnosis in DNHR. The assumption of proportional hazards was assessed graphically. Age (> 40 years vs. <= 40 years), CD4 count (>= 200 vs. < 200 cells/μl) and HIV-RNA (>= 105 vs. < 105 copies/ml) at diagnosis, gender, route of infection, centre and calendar time (diagnosed before vs. on or after 1 January 2000) were included in the analysis as categorical variables.
Patients registered in DNHR within three months of the date of their first HIV diagnosis according to DHCS were categorized as early registrations. Patients registered in DNHR more than three months after DHCS registration were considered late registrations. The mortality rate ratio (MRR) for the post three-month period was calculated for this group compared with the patients diagnosed later.
Data analysis was performed using SPSS statistical software, Version 15.0 (Norusis; SPSS Inc., Chicago, Illinois, USA). The study was approved by the Danish Data Protection Agency.