Articles
Associations between HIV and schizophrenia and their effect
on HIV treatment outcomes: a nationwide population-based
cohort study in Denmark
Marie Helleberg, Marianne G Pedersen, Carsten B Pedersen, Preben B Mortensen, Niels Obel
Summary
Background Associations between HIV and schizophrenia in people with and without substance use disorders and
the effect on timeliness of HIV diagnosis, antiretroviral therapy (ART), and treatment outcomes are poorly understood.
We aimed to assess the association between HIV and schizophrenia and the effect on HIV treatment outcomes in
people with and without substance use disorders.
Methods We did a population-based cohort study with data from nationwide registries in Denmark to investigate the
risk of schizophrenia after a diagnosis of HIV and the risk of HIV after a diagnosis of schizophrenia, accounting for
substance misuse, timeliness of HIV diagnosis, and treatment success in relation to schizophrenia. We selected the
cohort from people born in Denmark between Jan 1, 1955, and Dec 31, 1995, who we followed up from their 16th
birthday or Jan 1, 1995 (whichever occurred last) until their death, emigration from Denmark, onset of schizophrenia,
or Dec 31, 2011 (whichever came first). We estimated incidence rate ratios (IRRs) with Poisson and Cox regression,
with adjustment for calendar period, and age and its interaction with sex.
Findings We identified 2 786 286 individuals, of whom we included 2 646 154 people in analyses of risk of schizophrenia
diagnosis and 2 658 662 people in analyses of risk of HIV diagnosis. In 35 353 633 person-years of follow up, HIV was
associated with an increased risk of schizophrenia (IRR 4·09, 95% CI 2·73–5·83) and acute psychosis (7·15,
4·45–10·8); the IRR was highest within the first year of HIV diagnosis for both disorders (8·24, 2·95–17·7 and 12·7,
3·15–32·9, respectively). Schizophrenia was not associated with an increased risk of HIV in individuals without
substance misuse disorders (IRR 1·42, 95% CI 0·81–2·27). The risk of schizophrenia in individuals with HIV
decreased after ART (IRR 0·53, 0·32–0·87). The risk of acute psychosis did not differ between HIV-infected
individuals receiving antiretroviral regimens with and without efavirenz (IRR 0·70, 95% CI 0·32–1·54). We recorded
no differences in CD4 cell counts, time to ART, or viral suppression between individuals with schizophrenia with
HIV and those without schizophrenia when substance use was taken into account. Between 1999 and 2011, the
mortality rate ratio comparing HIV-infected individuals with schizophrenia with HIV-negative individuals without
schizophrenia was 25·8 (95% CI 18·8–34·3).
Interpretation Our findings emphasise the need for interventions to prevent HIV in people with schizophrenia,
especially for those with substance use disorders, and for accessible mental health services for individuals with HIV.
Funding Stanley Medical Research Institute, Lundbeck Foundation, Preben and Anna Simonsen Fund, Novo Nordisk
Foundation, The Danish AIDS Foundation, and the Augustinus Foundation.
Introduction
The prevalence of mental illnesses is higher in people
with HIV than in the general population.1–3 Few studies
have examined associations between HIV and severe
mental illnesses other than depression. HIV replication
in the CNS or opportunistic CNS infections might
increase the risk of mental illness.4 Some antiretroviral
drugs have neuropsychiatric side-effects, but their role in
the development of severe mental illness has not been
fully elucidated.5
People with mental disorders and concomitant
substance use disorders have an increased risk of HIV
acquisition.6 However, the association between mental
disorders and increased risk of HIV in the absence of
substance use is unclear. Mental disorders might affect
the timeliness of HIV diagnosis. People with substance
www.thelancet.com/hiv Vol 2 August 2015
Lancet HIV 2015; 2: 344–50
Published Online
July 3, 2015
http://dx.doi.org/10.1016/
S2352-3018(15)00089-2
See Comment page e314
Department of Infectious
Diseases, Copenhagen
University Hospital
(Rigshospitalet), Copenhagen,
Denmark (M Helleberg PhD,
Prof N Obel DrMed); Faculty of
Health Sciences, University of
Copenhagen, Copenhagen,
Denmark (M Helleberg,
Prof N Obel); National Centre
for Register-Based Research,
School of Business and Social
Sciences (M G Pedersen MSc,
C B Pedersen DrMedSc,
P B Mortensen DrMedSc) and
Centre for Integrated Registerbased Research, CIRRAU
(C B Pedersen, P B Mortensen),
Aarhus University, Aarhus,
Denmark; and the Lundbeck
Foundation Initiative for
Integrative Psychiatric
Research (iPSYCH), Aarhus,
Denmark (M G Pedersen,
C B Pedersen, P B Mortensen)
Correspondence to:
Dr Marie Helleberg, Department
of Infectious Diseases,
Copenhagen University Hospital
(Rigshospitalet),
2100 Copenhagen Ö, Denmark
marie.helleberg@regionh.dk
use disorders are likely to be tested for HIV more
frequently than are those with no substance use
disorders because of a known increased risk of HIV
transmission, whereas people with psychiatric
disorders, but no substance use disorders, might have
poor health-seeking behaviour and therefore face delays
in diagnosis of HIV. Substance misuse and depression
are associated with poor adherence to antiretroviral
therapy (ART).7 The importance of other severe
psychiatric disorders for initiation of and adherence to
ART is less well studied.
We did this study to examine whether people with HIV
have an increased risk of schizophrenia and acute
psychosis, independently of substance use, and to
examine associations between efavirenz and risk of
schizophrenia and acute psychosis. We used CD4 cell
e344
Articles
Research in context
Evidence before this study
We searched PubMed for articles examining associations
between HIV, severe mental illness, and substance use published
in English any time up to Oct 10, 2014. We used the search terms
“HIV”, “schizophrenia”, “acute psychosis”, “severe mental illness”,
“substance abuse”, “injection drug use”, and “antiretroviral
therapy”, and reviewed reference lists of the articles to ensure
completeness of our search. Previous studies have reported HIV
prevalences of 1–23% in people with severe mental illness, but
there is an absence of data for the temporal association.
Furthermore, disentanglement of the effects of substance
misuse in the reported associations has been difficult. Depression
is associated with poor adherence to antiretroviral therapy (ART)
but few data exist for treatment outcomes in people with HIV
who have other severe mental illnesses. Most studies have been
based on convenience samples, which increase the risk of
selection bias, or have been restricted by small sample sizes,
absence of adjustment for important confounders, or absence of
comparison groups. Studies based on administrative data have
been criticised for being subject to ascertainment bias.
Added value of this study
In this nationwide population-based study, including
2 658 662 people with a median follow-up time of 17 years, we
assessed temporal relations in associations between diagnoses
of HIV and schizophrenia in people with and without substance
counts and HIV-RNA to estimate the effect of
schizophrenia on risk of HIV acquisition and timeliness
of HIV diagnosis, ART initiation, and treatment
outcomes.
Methods
Study design and participants
See Online for appendix
e345
We did a nationwide population-based cohort study of
Danish residents, using data from national registries We
included people born in Denmark between Jan 1, 1955,
and Dec 31, 1995, who were residents of the country at
initiation of follow-up (from their 16th birthday or Jan 1,
1995, whichever occurred last). Individuals diagnosed
with schizophrenia before start of follow-up were
excluded.
Participants were classified as having schizophrenia
spectrum disorder (schizophrenia) and acute psychotic
disorder if they had been admitted to a psychiatric
department or had received outpatient care in a
psychiatric setting with these diagnoses (see appendix for
International Classification of Disease [ICD] codes).
Patients with substance use disorders were identified in
the National Patient Register and in the Psychiatric
Central Research Register. The date of onset was defined
as the date of the first contact (inpatient, outpatient, or
psychiatric emergency care unit) when a diagnosis of
interest was given.
misuse disorders. Individuals with HIV with and without
substance use disorders had an increased risk of schizophrenia
and acute psychosis. People with schizophrenia and no
substance use disorders did not have a significantly increased
risk of HIV acquisition. ART was associated with a decreased risk
of schizophrenia and acute psychosis. Our findings show that
high rates of virological suppression can be achieved irrespective
of severe mental illness in settings with a universal social
security system and free access to treatment. However, people
with HIV who have schizophrenia also have substantially
increased mortality, which might be related to substance abuse.
Implications of all available evidence
Present and previous studies emphasise the need for
interventions to prevent HIV in people with schizophrenia,
especially in those with substance use disorders, and that
mental health services should be easily available for individuals
infected with HIV. Our data suggest that early initiation of ART
might reduce risk of development of schizophrenia and acute
psychosis, and show that favourable treatment outcomes can
be achieved in people infected with HIV who have
schizophrenia. However, high mortality rates in this group call
for closer monitoring, focus on comorbidities, and treatment of
substance misuse. Further research to identify the causes of the
vast increase in mortality in people with HIV who have
schizophrenia is needed.
Data sources
The Danish Civil Registration System was established in
19688 and contains data for all Danish citizens. The
system includes information about, sex, date, place of
birth, and continuously updated information about vital
status.
The Danish Psychiatric Central Register, computerised
in 1969, contains data for all admissions to Danish
psychiatric inpatient facilities.9 The Danish National
Patient Register was established in 1977 and contains data
for all admissions to public hospitals in Denmark.10 In
both registers, information about outpatient visits was
included from 1995 onwards. From 1969 to 1993, the
diagnostic system used was the Danish modification of
ICD-8,11 and from 1994 to present, the system used was the
Diagnostic Criteria for Research accompanying ICD-10.12
The Danish HIV Cohort Study, described in detail
elsewhere,13 is a nationwide population-based study, which
includes all HIV-infected individuals treated at Danish
HIV centres after Jan 1, 1995. Individuals are identified by
staff on registration at the centres and consecutively
enrolled. Almost complete case capture is ensured by
linkage to laboratory records of CD4 cell counts and HIVRNA measurements done in HIV centres.
Data were linked with the unique personal
identification number used in all national registers to
enable accurate linkage on an individual level.
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Articles
Statistical analysis
To study the effect of HIV infection on risk of
schizophrenia, individuals were followed up from their
16th birthday or Jan 1, 1995 (whichever occurred last)
until their death, emigration from Denmark, onset of
schizophrenia, or Dec 31, 2011 (whichever came first).
Age, calendar period, history of substance misuse, and
time since HIV infection were treated as time-dependent
variables. To study the effect of schizophrenia on the risk
of HIV infection, we used a similar study design except
that time since onset of schizophrenia was used as the
exposure of interest.
Incidence rate ratios (IRRs) were estimated with loglinear Poisson regression and were adjusted for
calendar period, and age and its interaction with sex.
We used history of substance misuse as a potential
effect modifier. 95% CIs and p values were based on
likelihood ratio tests. We present only effect sizes of
analyses stratified by history of substance misuse,
because initial analyses without stratification showed
evidence of Simpson’s paradox. We used a Cox
proportional hazards model to estimate the effect of
ART on risk of schizophrenia or acute psychosis and
the effect of schizophrenia on time from HIV diagnosis
to initiation of ART in individuals with HIV, with
adjustment for sex and CD4 cell count at HIV diagnosis.
We used time since first positive HIV test as the
underlying timescale.
CD4 cell counts, HIV-RNA, and history of ART were
compared between people with HIV who had
schizophrenia and those without schizophrenia, with χ²
test for categorical variables and a Mann-Whitney rank
sum test for continuous variables. Analyses were
stratified by history of substance misuse.
Mortality rate ratios (MRRs) comparing time after a
diagnosis of HIV, schizophrenia, or a diagnosis of both
HIV and schizophrenia with time without a diagnosis of
HIV or schizophrenia were estimated by log-linear
Poisson regression adjusted for calendar period, age, and
sex. Because of results from a previous study showing a
marked decline in mortality in HIV-infected individuals
after 1998, analyses were stratified by calendar period:
1995–98 and 1999–2011.14
932 people with an HIV diagnosis before start of followup, leaving 2 646 154 in analyses of risk of schizophrenia
diagnosis and 2 658 662 people in analyses of risk of
HIV diagnosis. The median age at study inclusion was
21·4 years (IQR 16·0–30·5) and 1 355 918 (51%)
participants were men. Of 1369 participants diagnosed
with HIV during follow-up, 962 (59%) were men who
have sex with men (MSM), 451 (28%) acquired HIV
through heterosexual sex, and 172 (11%) were infected
through intravenous drug use.
During 35 353 633 person-years of follow-up, with a
median observation time of 17·0 years (IQR 9·8–17·0),
23 599 people developed schizophrenia (table 1). People
with HIV had a greater risk of schizophrenia than did
those without HIV (table 1). The IRR was 2·26 (95% CI
1·63–3·03) in 143 165 people with a history of substance
misuse and 4·09 (2·73–5·83) in 2 502 989 people without
substance use disorders (table 1). The increased risk of a
diagnosis of schizophrenia was substantially higher in
the first year after HIV diagnosis than in subsequent
years (table 1). The risk of acute psychosis was increased
in people infected with HIV, especially in the first year
after HIV diagnosis, and was increased in people both
with and without a history of substance misuse (table 2).
History of substance misuse
(n=143 165)
No history of substance misuse
(n=2 502 989)
Events Incidence* IRR† (95% CI)
(n)
Events (n) Incidence* IRR† (95% CI)
Overall
6128
50·05
··
17 471
5·12
··
No HIV diagnosis
6087
49·90
1
17 444
5·11
1
41
92·74
2·26 (1·63–3·03)
27
15·2
4·09 (2·73–5·83)
HIV diagnosis
Time since HIV diagnosis
<1 year
8
329·3
6·76 (3·09–12·6)
5
38·1
8·24 (2·95–17·7)
1–4 years
11
113·9
2·47 (1·28–4·24)
7
14·5
3·39 (1·45–6·.55)
≥5 years
22
68·48
1·75 (1·12–2·60)
15
12·9
3·81 (2·19–6·09)
IRR=incidence rate ratio. *Per 10 000 person-years at risk. †Adjusted for calendar year, and age and its interaction with sex.
Table 1: Incidences and IRRs of schizophrenia after a diagnosis of HIV, subdivided by history of substance misuse
History of substance misuse
(n=147 340)
No history of substance misuse
(n=2 509 232)
Events Incidence* IRR† (95% CI)
(n)
Events Incidence* IRR† (95% CI)
(n)
Overall
2670
20·29
··
6849
2·00
··
No HIV diagnosis
2635
20·10
1
6829
1·99
1
35
70·67
3·70 (2·60–5·08)
20
11·15
Role of the funding source
The funders of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report. The corresponding author had full
access to all the data in the study and had final
responsibility for the decision to submit for publication.
Results
We identified 2 786 286 people born in Denmark
between Jan 1, 1955, and Dec 31, 1995, of whom we
excluded 126 692 people who were not Danish residents
on their 16th birthday or on Jan 1, 1995; 13 440 people
with schizophrenia before start of follow-up; and
www.thelancet.com/hiv Vol 2 August 2015
HIV diagnosis
7·15 (4·45–10·8)
Time since HIV diagnosis
<1 year
9
3
22·69
1–4 years
9
324·1
82·10
15·5 (7·44–28·0)
4·04 (1·94–7·31)
3
6·18
12·7 (3·15–32·9)
3·62 (0·90–9·39)
≥5 years
17
47·50
2·55 (1·52–3·97)
14
11·90
8·09 (4·55–13·1)
IRR=incidence rate ratio. *Per 10 000 person-years at risk. †Adjusted for calendar year, and age and its interaction with sex.
Table 2: Incidences and IRRs of acute psychotic disorder after a diagnosis of HIV, subdivided by history of
substance misuse
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of HIV diagnosis and ART and response to ART (table 4).
We recorded no significant differences between
individuals with schizophrenia and those without
schizophrenia (table 4). More than 90% of individuals
without substance use disorders were virally suppressed
1 year after starting ART, irrespective of a previous
diagnosis of schizophrenia (table 4). Individuals with a
history of substance misuse had higher CD4 cell counts
at HIV diagnosis and were less likely to be virally
suppressed 1 year after initiation of ART than were those
without a history of substance misuse, irrespective of a
previous diagnosis of schizophrenia (p<0·0001 in both
analyses).
Between 1995 and 1998, people with HIV who had
schizophrenia were less likely to initiate ART than were
those without schizophrenia (IRR 0·42, 95% CI
0·13–0·99), but between 1999 and 2011, time to initiation
of ART did not differ between the two groups (1·00,
0·75–1·30).
After 1998, mortality rates were six to eight times higher
in people with HIV or schizophrenia than in those with
neither of these diagnoses (table 5). Furthermore, the risk
People with HIV receiving ART had a significantly
lower risk of being diagnosed with schizophrenia or
acute psychosis than did those with HIV who had not yet
started ART (appendix). The risk of being diagnosed with
schizophrenia or acute psychosis was not increased in
those starting an ART regimen including efavirenz
compared with those who received an ART regimen
without efavirenz (appendix).
During 35 711 623 person-years of follow-up, with a
median observation time of 17·0 years (IQR 10·0–17·0),
1639 people were diagnosed with HIV (table 3). In
148 107 people with a history of substance misuse,
schizophrenia was associated with an increased risk of
HIV diagnosis (table 3). In 2 510 555 people without a
history of substance misuse, those with schizophrenia
did not have a significantly increased risk of being
diagnosed with HIV (appendix). The increase in risk of
HIV in individuals with a history of substance misuse
decreased over time after the diagnosis of schizophrenia
(table 3).
In people who developed HIV during follow-up, we
assessed associations between schizophrenia and timing
History of substance misuse (n=148 107)
No history of substance misuse (n=2 510 555)
Events (n)
Incidence*
IRR† (95% CI)
Events (n)
Incidence*
Overall
282
2·09
··
1357
0·39
··
No schizophrenia
233
1·91
1
1342
0·39
1
49
3·70
1·75 (1·27–2·36)
15
0·61
1·42 (0·81–2·27)
Schizophrenia
IRR† (95% CI)
Time since diagnosis of schizophrenia
<1 year
5
6·24
3·39 (1·21–7·40)
··
··
1–4 years
15
4·91
2·45 (1·39–3·99)
··
4‡
0·53‡
1·53 (0·32–3·14)‡
≥5 years
29
3·09
1·43 (0·95–2·08)
11
0·64
1·45 (0·75–2·49)
IRR=incidence rate ratios *New cases per 10 000 person-years at risk. †Adjusted for calendar year and age and its interaction with sex. ‡Because of insufficient power, this
estimate refers to the time period of less than 5 years after onset with schizophrenia.
Table 3: Incidences and IRRs of HIV diagnosis after a diagnosis of schizophrenia, subdivided by history of substance misuse
History of substance misuse
Men
Age at HIV diagnosis (years)
CD4 count at HIV diagnosis (cells per μL)
No history of substance misuse
No schizophrenia Schizophrenia
(n=233)
(n=49)
p value
No schizophrenia
(n=1342)
156 (67%)
1200 (89%)
Schizophrenia
(n=15)
p value
13 (87%)
0·73
35 (71%)
0·54
36 (31–40)
34 (30–40)
0·50
35 (29–40)
41 (30–44)
0·19
450 (240–650)
440 (350–720)
0·41
360 (160–550)
330 (30–480)
0·26
0·13
CD4 count at ART initiation (cells per μL)
238 (140–330)
295 (180–350)
0·16
260 (135–370)
190 (70–310)
CD4 count 1 year after ART (cells per μL)
400 (270–520)
410 (300–760)
0·17
430 (290–580)
420 (250–470)
Initiated ART during follow-up
189 (81%)
Time from HIV diagnosis to ART initiation (months)
18 (1·2–51)
CD4 count <200 cells per μL for >3 months in absence of ART
24 (13%)
36 (73%)
0·23
25 (1·8–35)
0·93
8 (23%)
0·16
1185 (88%)
6·3 (0·9–32)
13 (87%)
0·28
0·85
0·7 (0·5–43)
0·43
194 (17%)
4 (29%)
0·28
HIV RNA >100 000 copies per mL at HIV diagnosis
57 (32%)
11 (31%)
0·78
472 (42%)
6 (50%)
0·62
HIV RNA >100 000 copies per mL at ART initiation
67 (38%)
13 (37%)
0·92
549 (49%)
6 (50%)
0·82
126 (80%)
27 (82%)
0·77
1034 (92%)
11 (92%)
0·97
HIV RNA <400 copies per mL 1 year after ART*
Data are n (%) or median (IQR), unless stated otherwise. ART=antiretroviral therapy. *In 1327 individuals who initiated ART more than 1 year before end of follow-up.
Table 4: Sex, age distribution, and indicators of timeliness of HIV diagnosis, ART initiation, and treatment response in people with HIV with and without
schizophrenia at time of HIV diagnosis, subdivided by history of substance misuse
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Articles
of death was substantially higher in people with both HIV
and schizophrenia than in those with neither of these
diagnoses or only one (table 5). The increase in risk did
not differ significantly between men (MRR 26·1, 95% CI
18·3–35·7) and women (24·7, 11·3–46·0). We had
insufficient statistical power to subdivide mortality
analyses by history of substance misuse.
Discussion
People with HIV had an increased risk of schizophrenia
and acute psychosis, especially in the first year after HIV
diagnosis. People with schizophrenia, but with no history
of substance misuse, did not have a significantly increased
risk of HIV infection. In HIV-infected individuals, the
risk of being diagnosed with schizophrenia decreased
after initiation of ART. The risk did not differ by exposure
to antiretroviral regimens with efavirenz versus those
without efavirenz. The timeliness in HIV diagnosis and
initiation of ART, and the likelihood of viral suppression
1 year after initiation of therapy, did not differ between
individuals with and without schizophrenia when history
of substance misuse was taken into account. Mortality
rates were more than 25 times higher in people with both
HIV and schizophrenia than in those without either of
these diagnoses, and were substantially higher than in
people with only HIV or schizophrenia.
The substantial increase in risk of a diagnosis of
schizophrenia within the first year after HIV diagnosis
might result from surveillance bias, because people
with mental illness might have been referred to
hospital-based psychiatric care only after they enrolled
in HIV care. However, the psychological distress
associated with an HIV diagnosis or the effects of HIV
replication in the CNS or opportunistic infections
might cause psychiatric illness.4 The increased risk of
schizophrenia persisted more than 5 years after HIV
diagnosis when most are receiving ART and virally
suppressed, when opportunistic infections are rare,
and when surveillance bias is unlikely to account for
the increase in risk of schizophrenia. We were unable
to assess the effect of behavioural and socioeconomic
factors on the association between HIV and
schizophrenia. Studies examining the risk of
schizophrenia in people with HIV are scarce,1 but our
findings are in agreement with a study of US military
personnel infected with HIV.15
ART was associated with a decreased risk of a
subsequent diagnosis of schizophrenia, which could be
explained either by treatment preventing the neurotoxic
effects of HIV replication or by people with HIV with
mental problems being less likely to initiate ART, for
example, because of attrition from HIV care. However,
our results did not suggest that people with schizophrenia
were significantly less likely to initiate ART than were
those without schizophrenia.
In the present study, HIV was associated with a
substantially increased risk of subsequent diagnosis of
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1995–98
1999–2011
Deaths Mortality*
No schizophrenia or
HIV
5996
Schizophrenia only
461
82
HIV only
211
580
47·2 (41·0–54·0)
15
874
76·5 (44·0–122)
Schizophrenia and
HIV
9
MRR† (95% CI)
1
7·66 (6·96–8·42)
Deaths
Mortality* MRR† (95% CI)
31 009
11
1
2749
85
6·24 (6·00–6·48)
263
142
43
416
8·19 (7·23–9·22)
25·8 (18·8–34·3)
MRR=mortality rate ratio. *Per 10 000 person-years at risk. †Adjusted for calendar year, and age and its interaction with sex.
Table 5: Mortality and MRRs after diagnoses of schizophrenia or HIV, or both, stratified by calendar period
acute psychosis, both in people with and in those without
a history of substance misuse, but the relative risk was
highest in those with substance use disorders. Several
case reports exist from the pre-ART era of acute
psychoses in individuals with advanced HIV/AIDS,
which were probably explained by opportunistic
infections, neurotoxic effects of HIV, or metabolic
disturbances caused by severe wasting.16 Encephalitis is a
rare complication of acute HIV infection or ART
interruptions.17 HIV encephalitis can present with
symptoms similar to acute psychotic disorder and
symptoms might therefore be misdiagnosed as mental
illness rather than as a manifestation of HIV. The
psychological distress associated with a diagnosis of HIV
might precipitate overt psychoses in susceptible people.
Efavirenz has neuropsychiatric side-effects such as
dizziness, insomnia, abnormal dreams, lethargy, and
depression.5 A few cases of acute psychosis with temporal
association with efavirenz have been reported.18 Whether
the association is causal or coincidental is unclear. We
recorded no increase in risk of acute psychoses associated
with efavirenz. Conversely, exposure to efavirenz versus
other antiretroviral drugs was associated with a tendency
towards reduced risk of acute psychosis. This finding
might be explained by channelling bias, such as people
with increased potential for mental problems might
preferentially have been prescribed alternative
antiretroviral drugs to avoid the well known CNS sideeffects of efavirenz.
The risk of being diagnosed with HIV was almost two
times higher in individuals with a diagnosis of
schizophrenia than in those without a diagnosis. Similar
to results of a study of Medicaid beneficiaries, we noted
that the risk of HIV was only significantly increased in
people with a history of substance misuse.19 The study of
Medicaid beneficiaries has been criticised for potential
bias caused by underascertainment of HIV infection in
people without substance use disorders.20 Because of the
long-term follow-up of median 17 years and the
nationwide design of our cohort study, the difference in
risk between individuals with a history of substance
misuse and those without is unlikely to be explained by
ascertainment bias. Behavioural factors might explain
this difference. Both intravenous drug use and use of
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non-injectable recreational drugs are associated with risk
of HIV. However, schizophrenia might also be associated
with inhibition and decreased sexual activity.21,22 We
obtained data for history of substance misuse through
hospital registries and might have missed some cases,
which could result in an overestimation of the risk of
HIV in absence of substance misuse. Schizophrenia did
not seem to affect the timeliness of HIV diagnosis, the
likelihood of initiating ART, or risk of treatment failure.
The Danish health-care system is characterised by free
and equal access to care and treatment and these results
might not be generalisable to settings in which absence
of health insurance can hinder access to care and
treatment.
People with both HIV and schizophrenia had a greatly
higher mortality than did those with only HIV or none of
these diagnoses. Because we recorded no differences in
CD4 cell counts or initiation or success of ART between
people with schizophrenia with HIV and those without
schizophrenia with HIV, the increase in mortality
associated with schizophrenia in HIV-positive people
seems to be linked to factors not directly related to HIV.
Unhealthy lifestyle (smoking, drinking alcohol, and
substance misuse), high prevalence of metabolic
syndrome, side-effects of antipsychotic drugs, late
diagnosis and insufficient treatment of comorbidities,
accelerated ageing, and high rates of suicide and accidents
account for the reduced life expectancy in people with
schizophrenia.23,24 The explanation for the increase in
mortality in people with HIV and schizophrenia could be
that some of these risk factors are exacerbated by HIV
infection or, alternatively, HIV infection might be a marker
for a susceptible subgroup of people with schizophrenia
with an increased rate of risk-taking behaviour and
unhealthy lifestyle. This notion is supported by the fact
that 78% of people with diagnoses of both HIV and
schizophrenia had a history of substance misuse.
Strengths of our study include the nationwide design
with prospective follow-up of all people who were born
between 1955 and 1995 and were Danish residents at
study inclusion. Information about people who developed
schizophrenia was based on clinical diagnoses, which
have been validated with good results.25,26 The Danish
HIV Cohort Study includes all individuals in the country
who have attended an HIV clinic.27 On the basis of the
completeness of Danish registries, migration and vital
status could be ascertained with high degree of certainty
and thus estimates are not biased by loss to follow-up.
Diagnoses of schizophrenia and of substance misuse
were captured through hospital-based registries only;
therefore, less severe cases might have been missed.
Furthermore, a lag period often occurs between
acquisition or onset of symptoms and diagnoses of HIV
and schizophrenia, which might affect results of
observational studies like ours. We did not have data for
socioeconomic factors and could not assess to what
degree these factors affect the observed associations
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between HIV and schizophrenia. Because we included
only people born in Denmark, results cannot be
generalised to immigrants, but exclusion of immigrants
also prevented the risk of bias caused by an increased risk
of psychiatric disorders associated with immigration.28
In summary, HIV infection is associated with increased
risk of schizophrenia and acute psychosis, whereas we
reported no significant increase in risk of HIV infection
in people with schizophrenia but without substance use
disorders. Schizophrenia does not seem to affect
timeliness of HIV diagnosis, ART initiation, or success
in settings with free access to health care, but cooccurrence of HIV and schizophrenia is associated with
substantially increased mortality. The high mortality
rates in this group call for closer monitoring, and further
research is needed to identify the causes of the vast
increase in this patient population.
Contributors
NO and PBM contributed to the conception of the study. All authors
contributed to the design of the study. MGP, CBP and MH did the
statistical analyses. All authors contributed to the interpretation of data.
MH drafted the manuscript, which was subsequently revised and
approved by all authors.
Danish HIV Cohort Study Centres
Departments of Infectious Diseases at Copenhagen University
Hospitals, Rigshospitalet (J Gerstoft, N Obel) and Hvidovre
(G Kronborg), Odense University Hospital (C Pedersen), Aarhus
University Hospital, Skejby (C S Larsen), Aalborg University Hospital
(G Pedersen), Herning Hospital (A L Laursen), Hilleroed Hospital
(L Nielsen), and Kolding Hospital (J Jensen).
Declaration of interests
We declare no competing interests.
Acknowledgments
This study was funded by Stanley Medical Research Institute, the
Lundbeck Foundation, Preben og Anna Simonsens Fond, Novo Nordisk
Foundation, The Danish AIDS Foundation, and the Augustinus
Foundation. We thank the staff of our clinical departments for their
continuous support and enthusiasm.
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