Utilization of psychotropic drugs prescribed to persons with and without HIV infection: a Danish nationwide population-based cohort study.

DOI: 10.1111/hiv.12135 HIV Medicine (2014), 15, 458–469

© 2014 British HIV Association

ORIGINAL RESEARCH

Utilization of psychotropic drugs prescribed to persons with and without HIV infection: a Danish nationwide population-based cohort study LD Rasmussen,1 D Obel,2 G Kronborg,3 CS Larsen,4 C Pedersen,1 J Gerstoft5 and N Obel5 Department of Infectious Diseases, Odense University Hospital, Odense, Denmark, 2Private Clinic of Child and Adolescent Psychiatry, Aarhus, Denmark, 3Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark, 4Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark and 5 Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

1

Objectives

The objective was to estimate the utilization of psychotropic drugs in HIV-infected individuals compared with that in the background population. Methods

Using data obtained from the Danish HIV Cohort Study and the Danish National Prescription Registry, we analysed aggregated data on redeemed prescription of psychotropic drugs during 1995–2009. We primarily focused our analyses on HIV-infected individuals with no history of injecting drug use (IDU) or hepatitis C virus (HCV) infection. Drug utilization was expressed as defined daily doses per 1000 person-days (DDD/1000PD). The utilization rate ratio (URR) was calculated as utilization in the HIV-infected cohort compared with that in the comparison cohort. We estimated longitudinal trends in utilization and potential associations with HIV and exposure to highly active antiretroviral therapy (HAART), especially efavirenz. Results

During 1995–2009, 54.5% of the HIV-infected cohort (3615 non-IDU/non-HCV-infected HIV-infected individuals) and 29.2% of the comparison cohort (32 535 individuals) had at least one prescription of a psychotropic drug. HIV infection was associated with a URR of 1.13 for antipsychotics, 1.76 for anxiolytics, 4.42 for hypnotics and sedatives, and 2.28 for antidepressants. Antidepressants were confined primarily to men who have sex with men (MSM). Older age, more recent calendar time, and increased time after HIV diagnosis were associated with increased drug utilization. However, no association with exposure to HAART or efavirenz was found. Conclusions

HIV-infected individuals had a higher utilization of psychotropic drugs than the background population, which was not confined to individuals with a history of IDU or HCV infection. This emphasizes the need to focus on diagnosis of, and appropriate psychopharmacological interventions for, mental disorders in this population. Keywords: antidepressants, antipsychotic drugs, anxiolytics, drug utilization, efavirenz, highly

active antiretroviral therapy, HIV, hypnotics and sedatives, pharmacoepidemiology, psychiatry Accepted 3 January 2014

Introduction Highly active antiretroviral therapy (HAART) has led to a dramatic decline in HIV-related morbidity and mortality [1] and transformed the disease into a chronic condition for which lifelong medication is necessary. Despite this,

Correspondence: Dr Line Dahlerup Rasmussen, Department of Infectious Diseases, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark. Tel: +45 65411321; fax: +45 66117418; e-mail: [email protected]

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HIV and use of psychotropic drugs 459

HIV-infected individuals have been found to have a high prevalence of psychiatric disorders, with rates exceeding those of the general population [2–6]. The estimates vary widely, possibly as a result of differences in the composition of the study populations and in diagnostic criteria. In addition, most studies include individuals with illicit drug use, which co-occurs significantly with psychiatric disorders [5,7]. Appropriate psychopharmacological interventions [8] are of utmost importance, as undiagnosed or inadequate treatment of psychiatric disorders may lead to poor healthrelated quality of life [9], poor adherence to HAART [10], and potentially accelerated HIV disease progression [11]. In general, there is little information on utilization of psychotropic drugs in HIV-infected individuals with no injecting drug use (IDU). As most cases of psychiatric disorders are diagnosed and treated outside hospitals, the actual prevalence in a population may be difficult to determine. We assumed that utilization of psychotropic drugs may act as a proxy for the presence of psychiatric disorders, and that the ratio between utilization of drugs in HIV-infected individuals and that in the general population may act as a measure of the relative risks of psychiatric disorders. We therefore performed a nationwide cohort study to investigate utilization of psychotropic drugs in HIV-infected individuals compared with an age- and gendermatched population-based comparison cohort.

Methods Setting As of 1 January 2010, Denmark had a population of 5.5 million, with an estimated HIV infection prevalence of 0.1% among adults [12,13]. Treatment of HIV infection is restricted to eight specialized centres where patients are seen on an out-patient basis at intended intervals of 12–24 weeks. Danish health care is universal and tax-funded, and antiretroviral treatment is provided free of charge. During the follow-up period of the study, national criteria for initiating HAART were HIV-related disease, acute HIV infection, pregnancy, CD4 cell count < 300 cells/μL until mid-2008 and 350 cells/μL thereafter and, until 2001, plasma HIV RNA > 100 000 HIV-1 RNA copies/mL.

Data sources We used the unique 10-digit personal identification number assigned to all individuals in Denmark at birth or upon immigration to link data from the following registries. The Danish HIV Cohort Study (DHCS) The DHCS, which has been described in detail elsewhere [14], is a nationwide, prospective, population-based cohort


study of all Danish HIV-infected individuals treated at Danish hospitals since 1 January 1995. The DHCS consecutively enrolls patients newly diagnosed with HIV and immigrants with HIV infection. The Danish Civil Registration System (DCRS) The DCRS, established in 1968, is a national registry that stores information on vital status, residency and migration for all residents of Denmark [15]. The Danish National Prescription Registry (DNPR) The DNPR, established in 1994, records individual-level data on all redeemed prescriptions dispensed at Danish community pharmacies, with complete data since 1 January 1995 [16]. The registry includes variables related to the drug, user, prescriber and pharmacy. The Anatomical Therapeutic Chemical Classification (ATC) code and number of defined daily doses (DDD) (as defined in the 2010 index) are established through a linkage to the World Health Organization’s (WHO) Collaboration Centre for Drug Statistics Methodology [17].

Study population HIV-infected cohort From the DHCS, we identified all Danish HIV-infected individuals aged 18 years or older at the index date who had been living in Denmark for at least 2 years. We defined the index date as the date of HIV diagnosis or 1 January 1995, whichever was more recent.

General population comparison cohort The comparison cohort consisted of nine age- and gendermatched population controls for each HIV-infected individual identified from the DCRS. Criteria for inclusion included being alive, being aged 18 years or older, and living in Denmark for at least 2 years prior to the index date. The index date for the comparison cohort was matched with that of the corresponding HIV-infected individual.

Outcome We analysed all redeemed prescriptions of psychotropic drugs in the observation period as classified by the ATC classification index (ATC codes: N05−N06: antipsychotics, anxiolytics, hypnotics and sedatives, lithium, antidepressants and centrally acting sympathomimetics – further details of codes and drugs are provided in Appendix S1). The quantity of the drug dispensed was defined as the drug utilization and expressed in terms of DDD per 1000 person-days, which is the unit of measurement approved

HIV Medicine (2014), 15, 458–469

460 LD Rasmussen et al.

by WHO [17]. The DDD is established from the declared content (strength) of the drug and corresponds to the estimated average adult daily maintenance dose used for the main indication of the drug [17]. Lithium and centrally acting sympathomimetics were only prescribed to 20 and 24 HIV-infected individuals, respectively, and were thus not subjected to further analysis.

Statistical analysis We computed the time from the index date until the date of death, emigration, loss to follow-up or 31 December 2009, whichever occurred first. Time was described in person-days (PD) and person-years (PY) of follow-up. We aggregated individual-level data for the use of psychotropic drugs as described above. The utilization rate ratio (URR) was determined as utilization in HIV-infected individuals divided by utilization in the comparison cohort. We calculated drug utilization and URR (1) for all individuals (HIV-infected individuals vs. individuals in the comparison cohort) and (2) for “treated individuals”, i.e. those individuals who redeemed at least one prescription of the given drug class during the defined period (URRTI). The first measure (URR) was used as a proxy for the relative utilization in the total population and the second (URRTI) as a proxy for the relative utilization in individuals prescribed the drug. As an overuse of psychotropic drugs is strongly associated with IDU [7] and hepatitis C virus (HCV) infection, independently of HIV coinfection or treatment with interferon/ribavirin [18], all further analyses were stratified by the presence of IDU and/or a positive HCV status. We primarily present the results for non-IDU/non-HCV-infected individuals. All analyses were performed individually for the four drug groups as defined above. We further stratified the analyses by gender, race, infection mode, and exposure to HAART and efavirenz. In addition, utilization and URR were calculated by calendar year (1995–2009) and five age intervals (≤ 30, > 30−40, > 40−50, > 50−60 and > 60). In a subanalysis, individuals with an index date after 1 January 1995 were followed for up to 2 years prior to the HIV diagnosis and annually after the diagnosis. We calculated the number of individuals exposed to the drug in the given period as well as the annual prevalence (the number of individuals exposed to the drug in the given period divided by the number of individuals who gave time to that year). Finally, we analysed differences in utilization of antipsychotics between groups by generation and drug potency and differences in utilization of antidepressants, anxiolytics, hypnotics and sedatives by drug class (Figs S1−3, Appendix S3) (subclassifications of the drugs are presented in Appendices S1 and S2). Data were analysed by means of descriptive statistical measures.


SPSS version 19.0 (SPSS Inc., Chicago, IL) was used for data analyses. Data from the DNHR and DNPR were obtained with approval of the Danish National Board of Health. The study was approved by the Danish Data Protection Agency (Journal No. 2008-41-1781).

Results The study cohort consisted of 4460 HIV-infected individuals and 40 140 comparison cohort individuals, of whom 81.1% (3615 and 32 535, respectively) had no history of IDU or HCV infection. Characteristics of the individuals are summarized in Table 1. In total, the study included 35 805 person-years of follow-up (PY) in the HIV-infected cohort and 413 372 PY in the comparison cohort (28 876 and 323 121 PY for non-IDU/non-HCV-infected individuals, respectively). During this period, 59.6% of the HIV-infected individuals and 29.7% of the comparison cohort were exposed at least once to a psychotropic drug (54.5% and 29.2% for non-IDU/non-HCV-infected individuals, respectively), and 146 907 and 377 504 prescriptions for psychotropic drugs, respectively, were filled (54 950 and 302 618, respectively, for non-IDU/non-HCV-infected individuals) (Table 1). In non-IDU/non-HCV-infected HIV-infected individuals, the drug class for which the highest percentage of individuals redeemed a prescription at least once was hypnotics and sedatives (37.8%) (Table 1). Antidepressants had the highest utilization (Table 2; full version in Table S1). IDU and HCV infection were strongly associated with high utilization of psychotropic drugs (Table 2). As we aimed to focus the study on use of psychotropic drugs that were not associated with IDU, and as IDU in Denmark is strongly associated with HCV infection, we excluded individuals with IDU and/or HCV infection from the remainder of the analyses. Utilization of antipsychotics was associated with female gender as well as non-Caucasian race (Table 2). Utilization of antidepressants was associated with MSM. In general, HAART was not associated with a major change in utilization of psychotropic drugs, and utilization did not differ by exposure to efavirenz (Table 2). In Figure 1, utilization and URR are shown by calendar year (1995–2009). For antipsychotics and antidepressants, utilization in general increased over time in both groups, whereas URR increased from 0.8 to 1.5 for antipsychotics and decreased from 2.8 to 2.0 for antidepressants. During the same period, utilization decreased for anxiolytics as well as hypnotics and sedatives. URR decreased from 3.1 to 1.8 for anxiolytics and from 7.0 to 3.8 for hypnotics. In Figure 2, utilization and URR are shown by age interval. Use of antipsychotics peaked in those aged 30–40

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Table 1 Characteristics of HIV-infected individuals and comparison cohort individuals

Age at index date (years) [median (IQR)] Male gender [n (%)] Caucasian race [n (%)] Infection mode MSM [n (%)] Heterosexual contact [n (%)] IDU [n (%)] Other/unknown [n (%)] HCV positive [n (%)] IDU and/or HCV infection [n (%)] HIV positive prior to 1995 [n (%)] AIDS prior to index date [n (%)] CD4 count at index date (cells/μL) [median (IQR)] Duration of follow-up (person-years) Duration of follow-up (years) [median (IQR)] Death during follow-up [n (%)] Emigration during follow-up [n (%)] Lost to follow-up [n (%)] HAART initiated prior to or during follow-up [N (%)] Person-years with no HAART Person-years with HAART Efavirenz initiated prior to or during follow-up [n (%)] Person-years with no efavirenz Person-years with efavirenz No. of redeemed prescriptions of psychotropic drugs No. who had been exposed to psychotropic drugs Antipsychotics Anxiolytics Hypnotics and sedatives Lithium Centrally acting sympathomimetics Antidepressants

All HIV-infected individuals

Comparison cohort individuals

Non-IDU/non-HCV-infected HIV-infected individuals

Comparison cohort individuals

(n = 4460)

(n = 40 140)

(n = 3615)

(n = 32 535)

38.0 (31.6–45.6) 3 590 (80.5) 3 913 (87.7) 2 217 (49.7) 1 416 (31.7) 542 (12.2) 285 (12.2) 781 (17.5) 845 (18.9) 1 833 (41.1) 440 (9.9) 272 (100–470) 35 804.8 7.81 (2.88–14.00) 1 230 (27.6) 104 (2.3) 9 (0.2) 3 443 (77.2) 10 918.3 24 886.5 2 434 (54.6) 23 045.2 12 759.6 146 807 2 657 (59.6) 619 (13.9) 1 517 (34.0) 1 920 (43.0) 20 (0.4) 24 (0.5) 1 348 (30.2)

38.0 (31.6–45.6) 32 310 (80.5) – – – – – – – – – – 413 371.8 12 00 (5.86–15.00) 2 059 (5.1) 648 (1.6) 30 (0.1) – – – – – – 377 504 11 911 (29.7) 2 239 (5.6) 5 770 (14.4) 5 870 (14.6) 146 (0.4) 123 (0.3) 6 540 (16.3)

38.6 (31.6–47.2) 2 999 (83.0) 3 120 (86.3) 2 104 (58.2) 1 291 (35.7) 0 (0) 220 (6.1) 0 (0) 0 (0) 1 355 (37.5) 369 (10.2) 260 (90–460.50) 28 875.8 7.71 (2.78–14.00) 838 (23.2) 90 (2.49) 8 (0.2) 2 833 (78.4) 8 024.4 20 851.4 2 067 (57.2) 18 050.6 10 825.2 54 950 1 970 (54.5) 348 (9.6) 971 (26.9) 1 365 (37.8) 19 (0.5) 18 (0.5) 1 011 (28.0)

38.6 (31.6–47.2) 26 991 (83.0) – – – – – – – – – – 323 121.4 11 13 (5.37–15.00) 1 778 (5.5) 515 (1.6) 25 (0.1) – – – – – – 302 818 9 498 (29.2) 1 793 (5.5) 4 575 (14.1) 4 668 (14.3) 116 (0.4) 101 (0.3) 5 199 (16.0)

The index date is the date of diagnosis of HIV infection or, if the patient was diagnosed before 1995, 1 January 1995. HAART, highly active antiretroviral therapy; HCV, hepatitis C virus; IQR, interquartile range; MSM, men who have sex with men; IDU, injecting drug user.

years for the HIV-infected cohort and in those aged 40–50 years for the comparison cohort. Use of anxiolytics, hypnotics and sedatives, and antidepressants increased with age for both groups, whereas the URR of antipsychotics, anxiolytics, and hypnotics and sedatives decreased with increasing age. For antidepressants, the URR showed very little variation across age intervals. Figure 3 presents drug utilization and URR by the time in years before (−2 to 0 years) and after (0−10 years) the HIV diagnosis. This subanalysis included 2251 non-IDU HIV-infected individuals and 20 259 matched comparison cohort individuals. Whereas utilization of antipsychotics rose steeply following the HIV diagnosis for the HIVinfected cohort, it was stable over the same period for the comparison cohort. URR thus increased from 0.4 to 2.0 in the period from 2 years before to 10 years after the HIV diagnosis. For anxiolytics as well as hypnotics and seda-


tives, utilization was already higher in the HIV-infected cohort than in the comparison cohort before the HIV diagnosis and further increased after HIV infection for hypnotics and sedatives, with a URR of 3.08. For the HIV-infected cohort, utilization of anxiolytics increased within the first year following HIV diagnosis (URR 2.2) and then levelled out before increasing again 8 years after the diagnosis. For both the HIV-infected cohort and the comparison cohort, utilization of antidepressants increased over time, with the URR 2 years before the HIV diagnosis being 1.2 and that 10 years after the diagnosis being 2.1. In general, a URRTI of approximately 1 was found, indicating that utilization of psychotropic drugs at the individual level did not differ substantially from that of the background population. Figures S1−S3 show utilization and URR by drug class and potency (Appendix S3).

HIV Medicine (2014), 15, 458–469


Table 2 Utilization of antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants Antipsychotics

Exposure

DDD/ 1000PD

URR

Anxiolytics

URRTI

All Comparison 12.76 Ref (1) Ref (1) HIV-infected 32.36 2.54 0.98 Presence of IDU/HCV infection Non-IDU/non-HCV-infected Comparison 13.39 Ref (1) Ref (1) HIV-infected 15.07 1.13 0.63 IDU and/or HCV-infected Comparison 10.51 Ref (1) Ref (1) HIV-infected 104.44 9.94 1.70 Including only non-IDU/non-HCV-infected individuals Gender Women Comparison 8.97 Ref (1) Ref (1) HIV-infected 28.83 3.21 1.76 Men Comparison 14.30 Ref (1) Ref (1) HIV-infected 11.99 0.84 0.47 Race Non-Caucasian Comparison 13.92 Ref (1) Ref (1) HIV-infected 28.15 2.02 1.08 Caucasian Comparison 13.31 Ref (1) Ref (1) HIV-infected 13.01 0.98 0.55 Infection mode Heterosexual Comparison 10.98 Ref (1) Ref (1) HIV-infected 17.84 1.62 1.00 MSM Comparison 14.80 Ref (1) Ref (1) HIV-infected 12.77 0.86 0.47 Other Comparison 13.05 Ref (1) Ref (1) HIV-infected 22.87 1.75 0.77 Time before HIV infection (−2 to 0 years) *Subpopulation Comparison 10.31 Ref (1) Ref (1) HIV-infected 4.05 0.39 0.33 No HAART/HAART No exposure to HAART Comparison 11.20 Ref (1) Ref (1) HIV-infected 8.98 0.80 0.50 Exposure to HAART Comparison 14.65 Ref (1) Ref (1) HIV-infected 17.41 1.19 0.73 No efavirenz/efavirenz No exposure to efavirenz Comparison 12.07 Ref (1) Ref (1) HIV-infected 17.11 1.42 0.77 Exposed to efavirenz Comparison 16.13 Ref (1) Ref (1) HIV-infected 11.67 0.72 0.50

Hypnotics and sedatives

Antidepressants DDD/ 1000PD

DDD/ 1000PD

URR

URRTI

DDD/ 1000PD

URR

URRTI

19.06 160.55

Ref (1) 8.42

Ref (1) 3.71

20.00 225.87

Ref (1) 11.29

Ref (1) 3.88

19.77 34.89

Ref (1) 1.76

Ref (1) 0.96

21.33 94.32

Ref (1) 4.42

16.50 684.20

Ref (1) 41.47

Ref (1) 10.36

15.22 774.11

19.58 33.61

Ref (1) 1.72

Ref (1) 1.17

19.81 35.18

Ref (1) 1.78

15.33 12.43

URR

URRTI

47.85 117.90

Ref (1) 2.46

Ref (1) 1.22

Ref (1) 1.69

48.19 109.91

Ref (1) 2.28

Ref (1) 1.20

Ref (1) 50.82

Ref (1) 12.31

46.64 151.22

Ref (1) 3.24

Ref (1) 1.29

18.46 54.47

Ref (1) 2.95

Ref (1) 1.36

72.45 76.65

Ref (1) 1.06

Ref (1) 0.76

Ref (1) 0.92

21.93 103.24

Ref (1) 4.71

Ref (1) 1.73

43.18 117.35

Ref (1) 2.72

Ref (1) 1.33

Ref (1) 0.81

Ref (1) 0.66

14.87 30.84

Ref (1) 2.07

Ref (1) 0.94

60.21 39.30

Ref (1) 0.65

Ref (1) 0.49

20.43 38.42

Ref (1) 1.88

Ref (1) 0.98

22.29 104.30

Ref (1) 4.68

Ref (1) 1.75

46.42 121.01

Ref (1) 2.61

Ref (1) 1.30

19.51 30.62

Ref (1) 1.57

Ref (1) 1.08

20.75 63.12

Ref (1) 3.04

Ref (1) 1.43

57,50 69,35

Ref (1) 1.21

Ref (1) 0.83

19.81 36.59

Ref (1) 1.85

Ref (1) 0.88

22.03 112.90

Ref (1) 5.13

Ref (1) 1.74

42,62 137,21

Ref (1) 3.22

Ref (1) 1.44

20.98 46.46

Ref (1) 2.21

Ref (1) 1.15

17.26 99.64

Ref (1) 5.77

Ref (1) 2.42

50,45 76,19

Ref (1) 1.51

Ref (1) 0.94

14.09 24.92

Ref (1) 1.77

Ref (1) 0.97

15.06 30.91

Ref (1) 2.05

Ref (1) 0.84

32.92 40.10

Ref (1) 1.22

Ref (1) 0.75

19.27 41.66

Ref (1) 2.16

Ref (1) 1.28

20.89 84.33

Ref (1) 4.04

Ref (1) 1.82

38.48 65.56

Ref (1) 1.70

Ref (1) 1.16

20.06 32.28

Ref (1) 1.61

Ref (1) 0.92

21.58 98.16

Ref (1) 4.55

Ref (1) 1.77

53.72 126.98

Ref (1) 2.36

Ref (1) 1.25

20.71 37.21

Ref (1) 1.80

Ref (1) 0.98

21.27 95.21

Ref (1) 4.48

Ref (1) 1.69

41.67 93.17

Ref (1) 2.24

Ref (1) 1.20

17.80 31.02

Ref (1) 1.74

Ref (1) 0.98

21.46 92.82

Ref (1) 4.32

Ref (1) 1.67

61.94 137.82

Ref (1) 2.23

Ref (1) 1.20

In a sub-analysis, individuals with an index date after 1 January 1995 (2251 non-IDU/non-HCV infected HIV-infected individuals and 20,259 matched comparison cohorts) were followed for up to two years prior to the HIV diagnosis and annually thereafter. *It only refers to these two lines and not the following (HAART, efavirenz etc.). Anatomical Therapeutic Chemical Classification (ATC) codes and definitions of antidepressants are given in Appendix S1. A fuller version of the table appears in Appendix S3 (Table S1). DDD, defined daily dose; PD, person-days; DDD/1000 PD, drug utilization; URR, utilization rate ratio; URRTI, utilization rate ratio in treated individuals; HAART, highly active antiretroviral therapy; IDU, injecting drug user; MSM, men who have sex with men; HCV, hepatitis C virus.


HIV Medicine (2014), 15, 458–469

Year

HIV-infected (DDD/1000 PD)


Comparison (DDD/1000 PD)


HIV-infected exposed, n


Comparison exposed, n


Annual prevalence HIV-infected (%)


Annual prevalence Comp. (%)


U liza on rate ra o (HIV-infected vs. comparison cohort)

DDD per 1000 person-days

Year

An depressants

(b)


An psycho cs

(a)



U liza on rate ra o

Year

Hypno cs and seda ves

(d)

Year













U liza on rate ra o

U liza on rate ra o



(c)


Anxioly cs


U liza on rate ra o

Fig. 1 Utilization and utilization rate ratio (URR) of psychotropic drugs by calendar year. Anatomical Therapeutic Chemical Classification (ATC) codes and definitions of antidepressants are given in Appendix S1. DDD, defined daily dose; PD, person-days; DDD/1000 PD, drug utilization; Comp., comparison cohort.

Discussion We found that HIV-infected individuals had a higher use of psychotropic drugs than the background population. No sign was found of higher utilization at an individual level (URRTI ∼ 1) in the non-IDU/non-HCV-infected population between HIV-infected individuals and the comparison cohort. As a result, the observed URRs serve as a measure of the relative risk of disorders. HIV-infected individuals had higher use of anxiolytics as well as hypnotics and sedatives both before and after HIV infection. However, older age, later calendar year, and longer time after HIV diagnosis were generally strongly associated with the use of psychotropic drugs. In addition, use of psychotropic drugs other than anxiolytics did not decrease following HAART and seemed unaffected by exposure to efavirenz.

Strengths The strengths of our study included use of a nationwide population-based cohort with long, complete follow-up as


well as access to high-quality Danish registries. Furthermore, access to valid, nationwide, individual-level data on all dispensed prescriptions since 1995 gave us the opportunity to examine longitudinal trends in utilization of psychotropic drugs and to estimate the relative risk of disorders, including those diagnosed and treated by nonpsychiatrists.

Limitations Although the completeness and quality of data from pharmacy databases are high and potentially superior to other measures of drug intake, the registry only captures prescriptions issued in the community. As psychiatric patients may be hospitalized for long periods, the total use of drugs might be under-enumerated. Also, the timing of redemption and consumption may not be exact. The DDD provided by WHO may not always reflect the formulations most often used and may not reflect the recommended or the prescribed daily dose (PD), therefore potentially leading

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Age

(b)

Age

≤30


An depressants

An psycho cs

(a)

≤30

HIV-infected (DDD/1000PD)


Comparison (DDD/1000PD)






Prevalence in HIV-infected


Prevalence in Comparison (%)


U liza on rate ra o

Age

≤30 ≤30

HIV-infected (DDD/1000PD) Comparison (DDD/1000PD) HIV-infected exposed, n Comparison exposed, n


Age


(d)



(c)


U liza on rate ra o

Anxioly cs

HIV-infected (DDD/1000PD) Comparison (DDD/1000PD) HIV-infected exposed, n Comparison exposed, n





U liza on rate ra o

U liza on rate ra o

Fig. 2 Utilization and utilization rate ratio (URR) of psychotropic drugs by age. Anatomical Therapeutic Chemical Classification (ATC) codes and definitions of antidepressants are given in Appendix S1. DDD, defined daily dose; PD, person-days; DDD/1000 PD, drug utilization; Comp., comparison cohort.

to systematic under-enumeration or over-enumeration. Importantly, we used the same source of data for both groups, why we presume that any misclassification may occur with an equal frequency in the groups, thus being non-differential. In the non-IDU/non-HCV-infected population, URRTI was approximately 1 for all drug categories, which indicates that consumption at the individual level in the HIV-infected group did not differ from that in the background population. This further demonstrates that URR is a valid proxy for relative risk of psychiatric disorders. The close monitoring of the HIV-infected population could increase the probability of diagnosis of, and hence prescription of medication for, psychiatric disorders. In addition, our comparison cohort, which was matched on age and gender, primarily consisted of young men who visited a general practitioner only infrequently. Thus, surveillance bias and bias as a result of lack of matching on sexual orientation may exist.


Psychiatric disorders and use of psychotropic drugs in association with HIV infection and HAART An American study by Vitiello et al. [19] estimated the use of psychotropic drugs in 2864 HIV-infected individuals in 1996 and found that 27.2% were treated with psychotropic drugs, of which antidepressants were the most frequently used. Although this study had information on psychiatric diagnosis, these diagnoses as well as use of medication were based on interviews regarding the past 6 months. Thus, it was subject to potential recall bias and could not evaluate trends over time. In comparison, we found that 54.2% of the non-IDU/non-HCV-infected HIV-infected individuals had been exposed to a psychotropic drug at least once. Through examination of indirect measures, we found a higher risk of psychiatric disorders in the HIV-infected population than in the comparison cohort, which is

HIV Medicine (2014), 15, 458–469

≤2-1

Time a er HIV infec on (years)

≤1-0

An depressants

(b)


DDD per 1000 person-days Time before HIV infec on (years)


An psycho cs

(a)

Time before HIV infec on (years) ≤2-1



Comparison (DDD/1000PD) HIV-infected exposed, n


Comparison exposed, n Annual prevalence in HIV-infected (%)



≤1-0



HIV-infected exposed, n Annual prevalence in HIV-infected (%) Annual prevalence in Comparison (%)

Annual prevalence in Comparison (%) U liza on rate ra o


≤1-0




(d) DDD per 1000 person-days



(c)



≤1-0


U liza on rate ra o

Anxioly cs








Annual prevalence in HIV-infected (%)

Annual prevalence in HIV-infected (%)

Annual prevalence in Comparison (%)

Annual prevalence in Comparison (%)

U liza on rate ra o

U liza on rate ra o

Fig. 3 Utilization and utilization rate ratio (URR) of psychotropic drugs by time before (−2 to 0 years) or after (≤ 10 years) HIV infection. Anatomical Therapeutic Chemical Classification (ATC) codes and definitions of antidepressants are given in Appendix S1. DDD, defined daily dose; PD, person-days; DDD/1000 PD, drug utilization; Comp., comparison cohort.

consistent with the results obtained by others [2–6]. However, a high prevalence of psychiatric disorders has also been found in association with other chronic medical conditions [20]. In addition, the psychopathology may predate the HIV infection and potentially be a risk factor for contracting HIV infection [5,21]. HIV infection may nevertheless lead to several neurological complications, such as HIV-associated neurocognitive disorders (HANDs), HIVassociated dementia (HAD), secondary neuroinfections, and lymphoma [22], which may increase the risk of initiation of therapy with psychotropic drugs. In addition, the health and social consequences of living with HIV include comorbidity and intake of multidrug regimens as well as emotional distress caused by fear of death, guilt, shame, loneliness, and ongoing stigmatization [23]. Although HAART may improve physical wellbeing and thereby decrease the level of psychological distress associated with the disease, our results showed no indications that HAART provides a protective effect. Contrary to our hypothesis, we found no indication of a higher utilization of psychotropic


drugs in association with exposure to efavirenz. However, awareness of the psychological side effects of efavirenz may have led the treating physician to exclude patients predisposed to mental illness from efavirenz treatment.

Trends in utilization of antipsychotics Our study confirms the findings of previous studies in the general population [24–27] of an increasing use of antipsychotics over the last two decades; in the present study, this increase was found in both cohorts. Although antipsychotics are primarily indicated for psychoses, new clinical applications such as depression, anxiety disorders, post-traumatic stress disorders (PTSDs), bipolar disorder, personality disorders, autism, delirium and dementia [28] may explain the expansion in their use. Furthermore, a lengthening of the duration of treatment [27] has been described. After the year 2004, we found a trend towards increased utilization relative to the general population. In addition, utilization seemed to be strongly associated with

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time after HIV infection but not with increasing age. This indicates an association with the duration of HIV infection, potentially as a result of sustained viral replication in the central nervous system (CNS), chronic inflammation, or factors such as ongoing emotional distress; however, the number of exposed individuals remained relatively small in the last years of observation. Importantly, we found that HIV infection was associated with higher utilization of antipsychotics in women than in men. This contrasts with the results of our analyses of other psychotropic drugs. However, as non-Caucasian race was also associated with higher utilization of antipsychotics, this could in part be attributable to the high prevalence of immigrants among HIV-infected women in Denmark. Refugees who may have experienced multiple traumatic events, who are forced to migrate and hence resettle in a new environment, and who may not integrate into society have been found to have a high prevalence of PTSD overlapping with anxiety and depression [29]. These disorders might be treated with antipsychotics. As the URRTI was 1.76 for women and 0.47 for men, this could indicate that the medication was used for indications other than psychosis in HIV-infected women, but adherence, length of treatment, and drug−drug interactions could also be the reason. Unfortunately, we cannot distinguish between prescriptions issued for different indications, which is why the estimates for antipsychotics may be subject to some imprecision.

Trends in the dispensing of anxiolytics and hypnotics and sedatives The primary indications for anxiolytics as well as hypnotics and sedatives are anxiety and insomnia, which have been described as highly prevalent in HIV-infected individuals and may accompany other psychiatric disorders [30]. However, in our study of a non-IDU/non-HCVinfected HIV-infected population, higher use was already detected prior to HIV infection. Anxiety and sleeping disorders have been described as more prevalent around the date of HIV infection [31], which seems consistent with our data, as well as at transition points in the disease, such as progression to AIDS or virological failure. Our results showed a significant drop in utilization of anxiolytics in the HIV-infected population in the late 1990s, potentially representing a change in the HIV prognosis as a result of the availability of HAART. For both cohorts, our results showed declining utilization in recent years, which may be a consequence of implementation of measures to reduce consumption, particularly of benzodiazepines, in Denmark [32]. Although utilization has decreased, HIV-infected individuals used 1.8 times more anxiolytics and 3.8 times more hypnotics and sedatives than did the comparison cohort in


2009. As utilization was strongly associated with increasing age, which is consistent with the research of others [33], this could lead to problems in an already aging HIVinfected population.

Trends in the dispensing of antidepressants The prevalence of depression in HIV-infected individuals has been described as 2–7 times that of the background population [3,23,34]. Indications for use of antidepressants have changed over time from major to mild depression to include stress, PTSD, anxiety disorders, eating disorders and neuropathic pain [35]. In addition, attention and public awareness of antidepressants have increased [24], and potentially an increasing tendency to treat patients over longer periods [36]. Alongside increased use of newer antidepressants, this may explain the increased utilization of antidepressants found for both cohorts in our study during 1995–2009, which is consistent with the trend found in other countries [24,26,37]. Although women accounted for the highest utilization of antidepressants in our study as well as in others [32], the utilization of antidepressants was not consistently higher than that of the comparison cohort, whereas the URR of antidepressants for HIV-positive men vs. HIV-negative men was 2.72. This is consistent with the results of Lopes et al. [4] Higher utilization of antidepressants in our study was largely confined to MSM. MSM have previously been found to have an increased risk of depression [23], which may be attributable to a number of psychosocial factors independent of HIV status and risk-taking behaviour in HIV-negative individuals [38]. In a Dutch study, MSM seemed to have an almost threefold increased prevalence of depression compared with non-MSM [39] as well as a higher prevalence of anxiety disorders and substance abuse. Although similar results have been obtained by others [40], no association between rates of depression and sexual orientation was found in a meta-analysis by Ciesla et al. [3] of the relationship between HIV infection and risk of depression. Consistent with previous results for the Scandinavian countries [32], utilization of antidepressants was strongly associated with age. As the HIV-infected population in our cohort is aging, this may to some extent explain the increasing trend with time since infection. Relative to the comparison cohort, utilization of antidepressant drugs decreased in the HIV-infected cohort from 1995 to 2009, which would be expected to be attributable to the introduction of HAART; however, such an effect could not be demonstrated in our analysis. In conclusion, older age, later calendar year, and longer time since HIV diagnosis were strongly associated with utilization of psychotropic drugs. This indicates that,

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although HAART has decreased somatic morbidity and HAD, the risk of psychiatric disorders is still very high. This emphasizes the need for a focus on diagnosis and treatment of mental disorders in this population.

2 Bing EG, Burnam MA, Longshore D et al. Psychiatric disorders and drug use among human immunodeficiency virus-infected adults in the United States. Arch Gen Psychiatry 2001; 58: 721–728. 3 Ciesla JA, Roberts JE. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry 2001; 158: 725–730.

Acknowledgements We are grateful to the staff of our clinical departments for their continuous support and enthusiasm. Conflicts of interest: NO has received research funding from Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Abbott, Boehringer Ingelheim, JanssenCilag and Swedish Orphan Drugs. CP has received funding from Abbott and Merck Sharp & Dohme. JG has received research funding from Abbott, Roche, Bristol-Myers Squibb, Mecrk Sharp & Dohme, Pharmasia, GlaxoSmithKline, Swedish Orphan Drugs and Boehringer Ingelheim. DO, CSL, GK and LDR report no conflicts of interest. Financial disclosure: We thank Preben and Anna Simonsen’s Foundation, Director Jacob Madsen and his wife Olga Madsen’s Foundation, the NOVO Nordic Foundation, University of Southern Denmark, and the Clinical Institute of the University of Copenhagen for financial support. Contributions to authorship: Conception and design: LDR, DO and NO. Analysis and interpretation of the data: LDR and NO. Drafting of the article: LDR. Critical revision of the article for important intellectual content: LDR, DO, CSL, CP, JG, GK and NO. Final approval of the article: LDR, DO, CSL, CP, JG, GK and NO. Provision of study materials or patients: CSL, CP, GK, JG and NO. Statistical expertise: LDR and NO. Obtaining of funding: NO, CSL, CP, GK and JG. Administrative, technical, or logistic support: LDR and NO. Collection and assembly of data: CSL, CP, GK, JG and NO.

4 Lopes M, Olfson M, Rabkin J et al. Gender, HIV status, and psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2012; 73: 384–391. 5 Beyer JL, Taylor L, Gersing KR, Krishnan KR. Prevalence of HIV infection in a general psychiatric outpatient population. Psychosomatics 2007; 48: 31–37. 6 Kilbourne AM, Justice AC, Rabeneck L, Rodriguez-Barradas M, Weissman S. General medical and psychiatric comorbidity among HIV-infected veterans in the postHAART era. J Clin Epidemiol 2001; 54 (Suppl 1): S22–S28. 7 Chander G, Himelhoch S, Moore RD. Substance abuse and psychiatric disorders in HIV-positive patients: epidemiology and impact on antiretroviral therapy. Drugs 2006; 66: 769–789. 8 Thompson A, Silverman B, Dzeng L, Treisman G. Psychotropic medications and HIV. Clin Infect Dis 2006; 42: 1305–1310. 9 Sherbourne CD, Hays RD, Fleishman JA et al. Impact of psychiatric conditions on health-related quality of life in persons with HIV infection. Am J Psychiatry 2000; 157: 248–254. 10 Wagner GJ, Goggin K, Remien RH et al. A closer look at depression and its relationship to HIV antiretroviral adherence. Ann Behav Med 2011; 42: 352–360. 11 Ickovics JR, Hamburger ME, Vlahov D et al. Mortality, CD4

Centres involved in the Danish HIV Cohort Study

12

Departments of Infectious Diseases at Copenhagen University Hospitals, Rigshospitalet (J. Gerstoft and N. Obel) and Hvidovre (G. Kronborg); Odense University Hospital (C. Pedersen); Aarhus University Hospitals, Skejby (C. S. Larsen) and Aalborg (G. Pedersen); Herning Hospital (A. L. Laursen); Hillerød Hospital (L. Nielsen); and Kolding Hospital (J. Jensen).

13

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Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Appendix S1 Anatomical Therapeutic Chemical Classification (ATC) codes and generic names of psychotropic drugs (N05−N06: antipsychotics, anxiolytics, hypnotics and sedatives, lithium, antidepressants, and centrally acting sympathomimetics). TCA, Tricicyclic antidepressants; SSRI, Selective serotonin reuptake inhibitors; MOA, Monoamine oxidase A inhibitors; NaSSA, Noradrenergic and specific serotonergic antidepressants; SNRI, Serotoninnoradrenalin resuptake inhibitors; NARI, Noradrenalin reuptake inhibitors. Appendix S2 Subclassification of antipsychotics by generation and potency of the drugs. TCA, Tricicyclic antidepressants; SSRI, Selective serotonin reuptake inhibitors; MOA, Monoamine oxidase A inhibitors; NaSSA, Noradrenergic and specific serotonergic antidepressants; SNRI, Serotoninnoradrenalin resuptake inhibitors; NARI, Noradrenalin reuptake inhibitors. Appendix S3 Figures S1−3 and Table S1.

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Fig. S1 Utilization and utilization rate ratio (URR) of antipsychotics by drug potency (low, medium and high). Fig. S2 Utilization and utilization rate ratio (URR) of anxiolytics and hypnotics and sedatives by drug class. TCA, Tricicyclic antidepressants; SSRI, Selective serotonin reuptake inhibitors; MOA, Monoamine oxidase A inhibitors; NaSSA, Noradrenergic and specific serotonergic antidepres-


sants; SNRI, Serotonin-noradrenalin resuptake inhibitors; NARI, Noradrenalin reuptake inhibitors. Fig. S3 Utilization and utilization rate ratio (URR) of antidepressants by drug class. Table S1 Utilization of antipsychotics, anxiolytics, hypnotics and sedatives, and antidepressants (this is a fuller version of Table 2)

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Use of psychotropic drugs following venous thromboembolism in youth. A nationwide cohort study.

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Tuberculosis and risk of cancer: a Danish nationwide cohort study.

Health care utilization in general practice after HPV vaccination-A Danish nationwide register-based cohort study.

Psoriasis and Sleep Apnea: A Danish Nationwide Cohort Study.

Why are psychotropic drugs prescribed to out-patients? A methodological study.

Psychotropic drugs and homicide: A prospective cohort study from Finland.

Five-year risk of HIV diagnosis subsequent to 147 hospital-based indicator diseases: a Danish nationwide population-based cohort study.

Cancer incidence among patients with a hospital diagnosis of pruritus: a nationwide Danish cohort study.

Long-term mortality in patients with pulmonary and extrapulmonary tuberculosis: a Danish nationwide cohort study.

Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study.

Smoking and renal function in people living with human immunodeficiency virus: a Danish nationwide cohort study.

Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population--A Nationwide Register Study.

Use of thyroid hormones in relation to pregnancy: a Danish nationwide cohort study.

Risk of psoriasis in patients with childhood asthma: a Danish nationwide cohort study.

Association of Rosacea With Risk for Glioma in a Danish Nationwide Cohort Study.

Adherence to methotrexate in rheumatoid arthritis: a danish nationwide cohort study.

Symptomatic venous thromboembolism following fractures distal to the knee: a nationwide Danish cohort study.

hyperactivity disorder drug treatment: a Danish nationwide drug utilization study.

Use of proton-pump inhibitors among adults: a Danish nationwide drug utilization study.

Use of corticosteroids during pregnancy and risk of asthma in offspring: a nationwide Danish cohort study.

Cholecystectomy in Danish children--a nationwide study.

Heart failure and risk of dementia: a Danish nationwide population-based cohort study.