After the implementation of highly active antiretroviral treatment (HAART) the life expectancy of HIV-infected individuals has increased substantially and HIV has turned into a chronic condition . Engagement in care is crucial for the prognosis of individuals infected with HIV. Regular monitoring is needed to determine when to initiate HAART [2,3]. Once initiated, HAART needs to be adhered to as interruptions are associated with poor prognosis  and with development of resistance [5,6]. On a public health scale engagement in care is important to reduce transmission of HIV [7–9].
Like in other chronic diseases retaining patients in care is a challenge. Several studies have evaluated adherence to drugs for patients with chronic as well as infectious diseases but few have been able to assess, on a population-based scale, the achievements of the healthcare system in retaining patients in care over prolonged periods of time.
The national registries in Denmark offer a unique opportunity, on a population-based scale, to identify HIV patients, evaluate loss to follow-up (LTFU) and to determine the rate of return to care, the proportion of time they are absent from care and to track and determine outcome for individuals LTFU. We aimed to assess retention of HIV patients in the Danish healthcare system over a 15-year period.
We estimated incidence and risk factors for LTFU (sub-study 1), incidence and prognostic factors for return to care (sub-study 2), mortality after LTFU and return to care (sub-study 3) and the proportion of time with retention in care (sub-study 4).
Denmark has a population of 5.5 million, with an estimated HIV prevalence of 0.09% among adults. HIV patients are treated in eight specialized HIV care centers and seen as outpatients at intended intervals of 12 weeks. Patients who miss a planned visit are reminded by letter specifying a date for a new appointment. Antiretroviral treatment is provided at the centers free of charge. The national criteria for initiating HAART have been described previously .
We used the 10-digit civil registration number assigned to all individuals in Denmark at birth or upon immigration to avoid multiple registrations and to link data from the following registers.
The Danish HIV Cohort Study, described in details elsewhere , is a population-based prospective nationwide cohort study of all HIV-infected individuals treated at Danish HIV centers after 1 January 1995. Data on vital status and migration were obtained from The Danish Civil Registration System , which is a national register established in 1967 that contains the demographic data of all Danish citizens. The Danish National Hospital Registry, established in 1977, collects information on all nonpsychiatric hospital admissions in Denmark. Since 1995, data from outpatient visits have been included. For each contact dates of admission and discharge are recorded .
The baseline date was defined as 365 days after the date of HIV diagnosis, date of immigration to Denmark or 1 January 1995, whichever was more recent.
A contact with the HIV care system was defined as an outpatient visit or an inpatient admission at one of the country's HIV care centers or measurement of CD4 cell count and/or viral load. Individuals were defined as having an episode of LTFU if they had no contact with the HIV care system for more than 365 days at any time after HIV diagnosis and had not died or emigrated in the 1-year period. The date of LTFU was defined as 365 days after their last contact. The date of return to care was defined as the date of the first contact with the HIV care system after an episode of LTFU.
We included all HIV-1-positive individuals in the Danish HIV Cohort study who were above 16 years of age at diagnosis, had a Danish civil registration number and attended a Danish HIV care center at least once between 1 January 1995 and 31 December 2008.
Incidence rates and mortality rates were calculated as number of events per 100 person-years (PYR) of observation time. Incidence rate ratios (IRRs) and mortality rate ratios (MRRs) were estimated using adjusted Poisson regression analyses. We included the following variables in the adjusted analyses: sex, age, origin (Denmark versus other), route of infection [heterosexual versus homosexual (men who have sex with men, MSM), injecting drug use (IDU) or other] and HIV diagnosis before 1995. Advanced HIV (AIDS or CD4 <200 cells/μl) and HAART were included as time-updated variables. In sub-studies 1 and 4 adjustment for calendar year of enrolment was included; calendar year of LTFU was included in sub-studies 2 and 4. The period after initiation of HAART was calculated from 365 days after HAART initiation, as the patients had attended care to receive HAART and therefore by definition could not be registered as LTFU the first year.
In sub-study 1 time was calculated from baseline to date of first episode of LTFU, emigration, death or 1 January 2010, whichever came first. Outcome was first episode of LTFU.
In sub-study 2 time was calculated from the date of first episode of LTFU until the date of return to care, emigration, death or 1 January 2010, whichever came first. Outcome was return to care. Probability of return to care was estimated using competing risk analysis with death and emigration as competing risks . Among individuals who returned to care incidence rate of a second episode of LTFU was estimated using Poisson regression analysis as described above.
In sub-study 3 time was calculated from baseline until 1 January 2010, emigration or death, whichever came first. Outcome was death and we calculated mortality rate for the following four periods: retention in care (from baseline until date of first episode of LTFU); LTFU (from date of first LTFU to date of return to care); less than 6 months after return to care; and at least 6 months after return to care. Mortality during retention in care was used as reference.
In sub-study 4 time was calculated from baseline until 1 January 2010, emigration or death, whichever came first. We first calculated the proportion of time with retention in care defined as the cumulative observation time, which was less than 12 months from last HIV care visit. Subsequently similar calculations were done with different cut-off values (2–24 months).
In all sub-studies the analyses were performed for the complete study period as well as for the periods before and after initiation of HAART. Thereby individuals could contribute observation time to periods before and after HAART.
The study was approved by the Danish Data Protection Agency. SPSS statistical software, Version 15.0 (Norusis; SPSS Inc., Chicago, Illinois, USA) and Stata, Version 8.0 (Stata Corporation, College Station, Texas, USA), were used for data analysis.
In the Danish HIV Cohort Study 4745 individuals fulfilled the inclusion criteria and were followed for 36 692 PYR between 1 January 1995 and 31 December 2009. The median follow-up time was 7.5 years [interquartile range (IQR) 3.2–13.0]. A total of 206 individuals had initiated HAART more than 1 year before enrolment in a Danish HIV care center and thus 4539 individuals contributed 11 344 PYR of observation time in the period before HAART initiation with a median follow-up time of 1.7 years (IQR 0.3–3.4). In the study period 3748 patients initiated HAART and contributed 25 348 PYR of observation time in the period after HAART initiation with a median follow-up time of 6.9 years (IQR 3.0–10.7). Characteristics of the study population are presented in Table 1.
Risk of loss to follow-up (sub-study 1)
The overall incidence rate for first episode of LTFU was 2.6/100 PYR [95% confidence interval (CI) 2.5–2.8], with incidence rate 6.1/100 PYR (95% CI 5.6–6.6) in the period before HAART initiation and incidence rate 1.2/100 PYR (95% CI 1.0–1.3) in the period after initiation of HAART. From 1 to 5 years after study inclusion the incidence rate of LTFU decreased from 5.4/100 PYR (95% CI 4.7–6.1) to 1.6/100 PYR (95% CI 1.2–2.2) in the complete study period, from 6.8/100 PYR (95% CI 6.0–7.8) to 3.5/100 PYR (95% CI 2.2–5.5) in the period before HAART initiation and from 1.7/100 PYR (95% CI 1.3–2.2) to 1.0/100 PYR (95% CI 0.7–1.6) in the period after HAART initiation (Fig. 1).
In the complete study period male sex [IRR 1.66 (95% CI 1.39–1.99)], Inuit [IRR 2.00 (95% CI 1.20–3.25)], African [IRR 1.28 (95% CI 1.03–1.60)] or ‘other’ origin [IRR 1.39 (95% CI 1.10–1.76)] and IDU [IRR 2.20 (95% CI 1.81–2.68)] were associated with LTFU, whereas older age [IRR 0.96 (95% CI 0.95–0.97) per 5 years increase], MSM [IRR 0.56 (95% CI 0.47–0.68)], HAART [IRR 0.69 (95% CI 0.60–0.81)] and advanced HIV [IRR 0.41 (95% CI 0.35–0.48)] were associated with lower risk of LTFU. In the periods before and after initiation of HAART trends were similar but not all associations were statistically significant (Table 2).
Return to care (sub-study 2)
The cumulative probability of return to care 1 year after LTFU was 0.58 (95% CI 0.54–0.61), 0.56 (95% CI 0.52–0.60) and 0.60 (95% CI 0.54–0.66) in the complete period and the periods before and after HAART initiation, respectively. Five years after LTFU the probability of return to care was 0.87 (95% CI 0.84–0.89) in the complete period and 0.87 (95% CI 0.84–0.90) and 0.86 (95% CI 0.81–0.91) in the periods before and after HAART initiation, respectively (Fig. 2).
In the complete period male sex [IRR 0.73 (95% CI 0.60–0.88)] and African origin [IRR 0.64 (95% CI 0.49–0.83)] were risk factors for not returning to care, whereas IDU [IRR 1.38 (95% CI 1.12–1.71)] and advanced HIV before LTFU [IRR 1.59 (95% CI 1.34–1.89)] were associated with increased likelihood of returning to care. Trends were similar in the periods before and after HAART initiation but not all associations were statistically significant (Table 2).
The incidence rates of a second episode of LTFU were 7.1/100 PYR (95% CI 6.2–8.2), 7.3/100 PYR (95% CI 6.2–8.5) and 7.5/100 PYR (95% CI 5.8–9.7) in the complete period and the periods before and after HAART initiation, respectively, and did not change significantly over time since first episode of LTFU (data not shown).
Among individuals who returned to care after LTFU, CD4 cell counts dropped median 50 cells/μl (IQR 2–122), 53 cells/μl (3–122) and 50 cells/μl (IQR 8–110) per year during absence from care in the complete period and the periods before and after HAART initiation, respectively. From LTFU to the time of return the proportion of individuals with CD4 cell count below 200 cells/μl increased from 12.9 to 29.7% in the complete period, from 7.6 to 23.2% in the period before HAART initiation and from 23.5 to 44.9% in the period after HAART initiation. Within 6 months after return, 1.4, 0.9 and 2.8% of individuals who returned to care were newly diagnosed with AIDS in the complete period and the periods before and after HAART initiation, respectively.
Mortality (sub-study 3)
The risk of death after LTFU was significantly increased compared to the period of retention in care: MRR 1.9 (95% CI 1.6–2.6), MRR 2.8 (95% CI 2.0–3.9) and MRR 1.7 (95% CI 1.2–2.3) in the complete period and the periods before and after HAART initiation, respectively.
The first 6 months after return to care mortality was substantial: MRR 10.9 (95% CI 5.9–19.9), MRR 5.4 (95% CI 2.4–11.9) in the period before HAART initiation versus MRR 10.6 (95% CI 3.5–31.9) in the period after HAART initiation. More than 6 months after return to care the risk of death was not different from the period of retention in care [MRR 1.3 (95% CI 0.9–1.9), 1.1 (95% CI 0.6–2.5) and MRR 1.3 (95% CI 0.6–2.9) in the complete period and the periods before and after HAART initiation, respectively].
Retention in care (sub-study 4)
The cumulative time of retention in care was 34 857 of 36 692 PYR (95.0%) in the complete study period, 10 641 of 11 344 PYR (93.8%) in the period before HAART initiation and 24 866 of 25 348 PYR (98.1%) in the period after HAART initiation. The proportion of observation time with more than 6 and 24 months since last HIV care visit was 9.9 and 2.8% in the complete study period; 12.0 and 3.6% in the period before HAART initiation; and 4.8 and 0.9% in the period after HAART initiation (Fig. 3).
In this nationwide study we found high rates of retention in a public healthcare system in which HIV treatment is highly specialized, centralized and free of charge.
The incidence rate of LTFU decreased significantly after initiation of HAART. Within 5 years after LTFU 87% returned to care. Risk factors for LTFU were male sex, young age, African, Inuit or ‘other’ origin, IDU and a previous episode of LTFU, whereas MSM, individuals on HAART and those with advanced HIV had lower risk of LTFU. Among individuals LTFU the probability of return to care did not differ in the periods before and after HAART initiation. HIV patients were retained in care 95% of the time, increasing to 98.1% after HAART initiation. HIV progressed during absence from care and mortality rates were significantly increased after LTFU and within 6 months after return.
Major strengths of this study are the nationwide, population-based design with long follow-up time. The unique Danish civil registration number allowed us to link several registers. Thus individuals who shifted between centers were not LTFU. In studies in which nationwide data are not available, both LTFU and survival may be overestimated [14–16]. We included several measurements to assess the frequency of HIV care to avoid overestimation of LTFU. Adherence to HAART was not evaluated and we were thus unable to analyze the relationship between nonadherence and LTFU. Measurement of retention in care is complex and several different methods have been used . The definition of LTFU used in this study is simple but enabled comparisons with other studies [14,18,19]. In addition we provided a more detailed illustration of retention in care (Fig. 3).
Since resources and organization of the healthcare system influence retention in care, our results may not be generalizable to other countries but demonstrate what can be achieved in a high-income country with well structured HIV care.
Other studies have reported proportions of LTFU of 8.5–38.8% [14,18–22]. The length of the follow-up periods, which varied from 1 to 10 years, as well as differences in healthcare systems and characteristics of the study populations are likely to influence these estimates. In Denmark treatment is free of charge and there is access to HIV care in all regions, which is why lack of health insurance and geographical distance to access care are not limiting factors.
As documented in other studies young individuals, migrants and IDUs had poor retention in care, whereas MSM and individuals on HAART were more likely to be engaged in care [14,18–20]. With increasing efforts to diagnose HIV at an early stage, more focus may be needed to retain young asymptomatic patients in care .
Individuals on HAART need to attend the clinic to receive medicine, which may partly explain the lower risk of LTFU in the period after HAART initiation. Individuals with poor engagement in care may be less likely to initiate HAART because they opt out or because of hesitance to prescribe treatment. In some cases longer intervals between visits may have been intended before versus after HAART initiation, but this does not explain the major differences in gaps in care.
Our finding of high rates of retention in care after initiation of HAART may explain the low incidence rate of acquired HIV drug resistance , the low number of HIV patients at risk of transmitting drug-resistant virus  and few cases of transmitted drug resistance in Denmark .
In the HAART era the life expectancy of HIV patients has increased substantially . Age-related diseases contribute increasingly to morbidity and non-AIDS-related causes now account for approximately half of the mortality [28,29]. To reduce morbidity and mortality further, engagement in care is crucial for prevention and treatment of these non-HIV-related conditions.
Loss to follow-up was associated with progression of HIV and the mortality rate after LTFU was significantly increased among treatment-naive individuals. After HAART initiation the mortality rate was almost doubled among individuals LTFU compared to those retained in care. Unmeasured confounders, that is socioeconomic factors may explain part of the increased mortality. The estimate of excess mortality after LTFU among individuals on HAART is similar to that reported by Giordano et al. who evaluated survival the first year after HAART initiation. However, the two studies are not directly comparable due to differences in definition of retention in care and study period.
A significant proportion of those, who returned to care after LTFU, only did so when they were severely immunosuppressed and the mortality rate within 6 months after return was more than 10 times that of individuals retained in care. This is in accordance with findings from a French study  and suggests that early tracking and re-engagement in care of individuals LTFU should be considered in settings in which it is feasible.
We conclude that high rates of retention can be achieved in a healthcare system with free access to treatment and is associated with a favorable outcome. HIV patients LTFU should be intensively tracked as return to care is associated with decreased morbidity and mortality.
We thank the staff of our clinical departments for their continuous support and enthusiasm.
All of the authors contributed to the conception and design of the study and/or the analyses and interpretation of the data. The manuscript was drafted by M.H., F.N.E., J.G. and N.O. and was critically reviewed and subsequently approved by all authors.
No funding sources were involved in study design, data collection, analysis, report writing, or the decision to submit the paper.
Centers in the Danish HIV Cohort Study:
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).
Conflicts of interest
N.O. has received research funding from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, Janssen-Cilag, and Swedish Orphan. C.P. has received research funding from Abbott, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Swedish Orphan, Jansen Pharma/Tibotec and Boehringer Ingelheim. J.G. has received research funding from Abbott, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, ViiV, Swedish Orphan and Gilead, M.H., F.N.E., G.K, C.S.L. and G.P. report no conflicts of interest.
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