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JNNP Online First, published on August 4, 2014 as 10.1136/jnnp-2014-307932
Multiple sclerosis

RESEARCH PAPER

HIV and lower risk of multiple sclerosis: beginning
to unravel a mystery using a record-linked database
study
Julian Gold,1,2 Raph Goldacre,3 Hubert Maruszak,1,2 Gavin Giovannoni,2
David Yeates,3 Michael Goldacre3
▸ Additional material is
published online only. To view
please visit the journal online
(http://dx.doi.org/10.1136/
jnnp-2014-307932).
1

The Albion Centre, Prince of
Wales Hospital, Sydney, New
South Wales, Australia
2
Centre for Neuroscience and
Trauma, The Blizard Institute
of Cell and Molecular Science,
Queen Mary University of
London, London, UK
3
Unit of Health-Care
Epidemiology, Nufﬁeld
Department of Population
Health, University of Oxford,
Oxford, UK
Correspondence to
Dr J Gold, The Albion Centre,
Prince of Wales Hospital,
Sydney, NSW 2029, Australia;
julian.gold@sesiahs.health.
nsw.gov.au
Received 20 February 2014
Revised 13 June 2014
Accepted 14 June 2014

ABSTRACT
Objectives Even though multiple sclerosis (MS) and
HIV infection are well-documented conditions in clinical
medicine, there is only a single case report of a patient
with MS and HIV treated with HIV antiretroviral
therapies. In this report, the patient’s MS symptoms
resolved completely after starting combination
antiretroviral therapy and remain subsided for more than
12 years. Authors hypothesised that because the
pathogenesis of MS has been linked to human
endogenous retroviruses, antiretroviral therapy for HIV
may be coincidentally treating or preventing progression
of MS. This led researchers from Denmark to conduct an
epidemiological study on the incidence of MS in a newly
diagnosed HIV population (5018 HIV cases compared
with 50 149 controls followed for 31 875 and 393 871
person-years, respectively). The incidence rate ratio for
an HIV patient acquiring MS was low at 0.3 (95% CI
0.04 to 2.20) but did not reach statistical signiﬁcance
possibly due to the relatively small numbers in both
groups. Our study was designed to further investigate
the possible association between HIV and MS.
Methods We conducted a comparative cohort study
accessing one of the world’s largest linked medical data
sets with a cohort of 21 207 HIV-positive patients and
5 298 496 controls stratiﬁed by age, sex, year of ﬁrst
hospital admission, region of residence and
socioeconomic status and ‘followed up’ by record
linkage.
Results Overall, the rate ratio of developing MS in
people with HIV, relative to those without HIV, was
0.38 (95% CI 0.15 to 0.79).
Conclusions HIV infection is associated with a
signiﬁcantly decreased risk of developing MS.
Mechanisms of this observed possibly protective
association may include immunosuppression induced by
chronic HIV infection and antiretroviral medications.

▸ http://dx.doi.org/10.1136/
jnnp-2014-308297

INTRODUCTION

To cite: Gold J, Goldacre R,
Maruszak H, et al. J Neurol
Neurosurg Psychiatry
Published Online First:
[please include Day Month
Year] doi:10.1136/jnnp2014-307932

Even though multiple sclerosis (MS) and HIV infection are two of the most documented conditions in
clinical medicine, with more than one million peerreviewed papers combined, there is only a single
case report of a patient with MS and HIV treated
with HIV antiretroviral therapies.1 In this case
report, the patient’s MS symptoms resolved completely after starting combination antiretroviral
therapy (cART) and remain subsided for more than
12 years of follow-up. In the report, the authors
hypothesised that because the pathogenesis of MS

Gold
J, et al. J Neurol
Neurosurg
Psychiatry(or
2014;0:1–4.
doi:10.1136/jnnp-2014-307932
Copyright
Article
author
their employer)
2014. Produced

has been linked to several human endogenous retroviruses (HERVs),2 3 antiretroviral therapy for
HIV may be coincidentally treating or preventing
progression of MS. Publication of this report led
investigators from Denmark to conduct an analysis
of the incidence of MS in a newly diagnosed HIV
population by utilising the Danish National
Registry of Patients (1994–2011), which is linked
to Civil Registration System and the Danish MS
Registry. Their analysis determined that among
5018 ﬁrst presenting HIV patients and 50 149 controls, matched for age and sex and followed for
31 875 and 393 871 person-years, respectively, the
incidence rate ratio (IRR) for an HIV patient
acquiring MS was 0.3 (95% CI 0.04 to 2.20). This
IRR did not reach statistical signiﬁcance, possibly
due to the relatively small numbers of people who
developed MS in each group.4 These authors also
suggested that HIV therapies may be coincidentally
ameliorating the MS and that, if so, this could
provide an explanation for the relatively large
observed protective effect of HIV on the development of MS. This was the ﬁrst record linkage study
exploring an association between HIV and MS. In
order to further test this hypothesis, we explored
one of the world’s largest linked medical data sets
to investigate the possible relationship between
HIV and developing MS.

METHODS
We analysed a national linked data set of English
Hospital Episode Statistics (HES) to identify all
people with HIV who were discharged from
National Health Service hospitals, between 1999
and 2011, as a hospital day-patient or inpatient,
irrespective of the reason for this contact. HIV was
recorded on the chart, even though the contact
may have been for a condition unrelated to HIV.
Successive discharge records relating to the same
person were linked together as a cumulative statistical record for that person, and these were linked
to any death record. HES was provided by the
English National Health and Social Care
Information Centre; death records were provided
by the Ofﬁce for National Statistics. All data were
anonymised by encryption of personal identiﬁers
before being supplied to the Oxford study team for
record linkage. The statistical analysis was carried
out using analytical software designed within the
Oxford research unit using the statistical analysis
software package SAS (release V.9.2, SAS Institute

by BMJ Publishing Group Ltd under licence.

1

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Multiple sclerosis
Inc, Cary, North Carolina, USA). Additional statistical methodology is explained more fully and referenced in the online supplementary appendix.
The earliest record of HIV in HES was the record used for
analysis. Having identiﬁed all people in the data set with HIV,
we stratiﬁed them into 5-year age bands, sex, year of ﬁrst hospital admission, region of residence and quintiles of Index of
Multiple Deprivation (a standard national measure of socioeconomic status). We then ‘followed up’ these people, through
record linkage until 31 December 2011, for any subsequent
record of MS. Anyone who had a record of MS prior to or concurrent with the HIV record was excluded from the cohort.
This excluded ﬁve people with prior MS and three people with
a simultaneous record of HIV and MS.
For comparison, we also identiﬁed a cohort of people
without HIV. These were hospital controls selected from our
data set; they comprised all people in HES from 1999 to 2011
whose principal reason for an episode of care was for a minor
medical or surgical condition or injury (the earliest, for any individual person, of any of those listed in the footnote to table 1).
We stratiﬁed this cohort in the same way as the HIV cohort, and
‘followed up’ this cohort, too, for any subsequent record of MS.
As with the HIV cohort, anyone with a record of MS prior to
or at the same time as the ﬁrst admission for a reference

Table 1 Age distribution of people entering the HIV cohort, the
percentage who were female, and the number of people who
entered the reference cohort*
Age
(years)

HIV cohort
Number
(% of total)

0–4
5–9
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
85+
All ages

139
168
138
173
653
2136
4066
4792
3701
2228
1293
776
480
274
98
37
22
33
21 207

(0.7)
(0.8)
(0.7)
(0.8)
(3.1)
(10.1)
(19.2)
(22.6)
(17.5)
(10.5)
(6.1)
(3.7)
(2.3)
(1.3)
(0.5)
(0.2)
(0.1)
(0.2)
(100)

Female
(%)

Reference
cohort
Number

44.6
45.2
57.2
59.0
44.4
43.9
36.9
29.6
24.9
20.6
18.6
17.4
16.3
21.2
21.4
27.0
22.7
45.5
30.2

112 355
145 618
113 372
166 198
200 079
264 771
377 462
444 962
390 356
329 573
345 117
375 702
377 503
387 109
397 229
385 998
282 933
202 159
5 298 496

Note that all eligible controls were used (there is no merit in discarding controls to
equalise numbers in each age group); and that all analyses were done within strata
(eg, the 112 355 controls aged 0–4 were compared with the 139 in the HIV cohort).
The expected numbers in each stratum were then summed to give age-standardised
comparisons of expected and observed numbers with MS in each cohort.
*The reference cohort consisted of people admitted with the following conditions
coded under the Office of Population, Censuses and Surveys code (OPCS) edition 4
for operations and the ICD revision 10 for diagnoses: adenoidectomy (OPCS4 E20),
tonsillectomy (F34+F36), appendectomy (H01–H03), total hip replacement (W37–
W39), total knee replacement (W40–W42), cataract (ICD 10 H25), otitis externa/
media (H60–H67), varicose veins (I83), haemorrhoids (I84), deflected septum, nasal
polyp ( J33+J34.2), inguinal hernia (K40), gallbladder disease (K80–K81), in–growing
toenail and other diseases of nail (L60), sebaceous cyst (L72.1), bunion (M20.1),
internal derangement of knee (M23).
MS, multiple sclerosis.

2

condition was excluded from the reference cohort. This
excluded 877 people with prior MS and 1767 people with a
simultaneous record of a reference condition and MS.
Expected numbers of people with MS were determined in
each stratum of each cohort, by calculating the rate of MS in the
combined population of the HIV and reference cohorts, based
on person-days at risk; we then applied that rate to the persondays at risk in the corresponding stratum in, ﬁrst, the HIV
cohort and, second, the reference cohort. This gave stratumspeciﬁc expected numbers of people with MS in the HIV and
the reference cohort. The expected numbers were added to give
all-strata totals in each cohort, which were compared with the
observed numbers. Stratum-standardised summary estimates of
relative risk were then calculated according to standard statistical
practice described elsewhere.5 The rate ratio (RR) was calculated
using the formula (OHIV/EHIV):(Oref/Eref ), where the Os and Es
are the observed and expected numbers of people with MS in,
respectively, the HIV cohort and the reference cohort.
Subanalyses were performed, restricting the outcome of MS
to include only the people whose ﬁrst record of MS, known to
us, was more than a year, and then more than 5 years, after the
ﬁrst record of HIV. The reason for this was to identify the
sequence of HIV occurring before MS as best we could. In addition, we performed separate analyses for each ethnic group.

RESULTS
The total number of people who entered the HIV cohort was
21 207 (152 618 person-years at risk); the total number of
people who entered the reference cohort was 5 298 496
(39 998 613 person-years at risk). The median follow-up period
for the HIV cohort was 2454 days (IQR 1790 days); the median
follow-up period for the reference cohort was 2756 days (IQR
1951 days). Table 1 shows the age distribution of the HIV
cohort, the percentage who were women, and the number of
people who entered the reference cohort. The distribution of all
other variables by which we stratiﬁed the cohorts in the analyses
are shown in the online supplementary appendix table. Overall,
the RR of MS in people with HIV, relative to those without
HIV, was 0.38 (95% CI 0.15 to 0.79), based on 7 observed and
18.3 expected cases (table 2). Restricting the outcome to
include only the people whose ﬁrst record of MS, known to us,
was more than a year after the ﬁrst record of HIV, the RR was
0.25 (95% CI 0.07 to 0.65), based on 4 observed and 15.8
expected cases. Restricting the outcome to include only the
people whose ﬁrst record of MS was more than 5 years after the
ﬁrst record of HIV, the RR was 0.15 (95% CI<0.01 to 0.83),
based on 1 observed and 6.7 expected cases (table 2).

Table 2 Observed (MS obs) and expected (MS exp) numbers of
people in the HIV cohort who had a subsequent record of multiple
sclerosis (MS), shown by age at entry to the HIV cohort and by time
interval from the first HIV record to the first MS record; rate ratios
and 95% CIs
Age at entry to
HIV cohort (years)

Time interval
(years)

MS obs

MS exp

RR (95% CI)

All
All
All
<45

All
1+
5+
All

7
4
1
3

18.3
15.8
6.7
13.9

0.38
0.25
0.15
0.22

(0.15 to 0.79)
(0.07 to 0.65)
(<0.01 to 0.83)
(0.04 to 0.63)

Gold J, et al. J Neurol Neurosurg Psychiatry 2014;0:1–4. doi:10.1136/jnnp-2014-307932

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Multiple sclerosis
When conﬁning the analysis to people whose ethnicity was
recorded as White British, the RR was 0.37 (95% CI 0.08 to
1.08), based on 3 observed and 8.1 expected cases in the HIV
cohort. When we conﬁned the analysis to other ethnic groups,
numbers were small. Furthermore, data on ethnicity were often
recorded as ‘not known’ or not recorded at all. Combining all
other speciﬁed ethnic groups, there were 1 observed and 6.8
expected MS cases in a cohort of 5353 people; where ethnicity
was either recorded as ‘not stated’ or where ethnicity was not
recorded at all, there were three observed and four expected
cases in an HIV cohort of 10 849 people.

Sensitivity analyses
We repeated the analyses including the cases with MS on the
ﬁrst record of HIV or reference condition. The observed
number of cases of MS in the HIV cohort rose to 10, the
expected to 22.4, and the RR was 0.45 (0.21–0.82). We re-ran
the analyses excluding people aged 70 and over from both
cohorts in case the upper age groups, with fewer people, had
any distorting effect. The RR was 0.34 (0.12–0.74), based on 6
observed and 17.7 expected cases.

DISCUSSION
Our ﬁndings are consistent with the national study in Denmark,
but, crucially, given the size of the cohorts in the exposure as
well as control groups in our study, the negative association
between HIV and MS was statistically signiﬁcant. If subsequent
studies demonstrate there is a causal protective effect of HIV
(and/or its treatment), and if the magnitude of it proves to be
similar to our rate ratio of 0.38, this would be the largest protective effect of any factor, yet observed in relation to the development of MS. Previous studies have shown that factors such as
smoking,6–8 speciﬁc gene markers,9 10 vitamin D deﬁciency11 12
and many different viruses13–16 increase the risk of either
acquiring MS or of MS progressing, compared with controls.
However, not having these risks may not be protective if the
relative risk, compared with the general population, simply
returned to 1.
There are several possible explanations for the observed association in our study.
First, immunodeﬁciency induced by HIV itself (even in the
absence of antiretroviral treatment) may prevent development of
MS. HIV impairs immune cell homoeostasis and targets a wide
range of immune cells and signalling pathways overlapping with
MS pathogenesis. Second, antiretroviral medications used to
suppress HIV replication potentially may suppress other viral
pathogens implicated in MS, for instance HERVs and herpes
viruses.17
If having HIV is associated with a signiﬁcantly lower risk of
subsequent MS and the association is in the causal chain, it is
either because of some biological effect of HIV itself on the
pathogenesis of MS, or because the treatment for HIV are coincidentally also treating or preventing development of MS.
Unfortunately, neither this study nor any study design that is
feasible at present can prove which mechanism may be correct.
However, we have made some reasonable assumptions, below,
to assist in furthering this issue.
The pendulum of when to start HIV therapy has swung over
the past two decades from early treatment, in order to preserve
the remaining CD4 cells to later treatment, when it was
observed that the CD4 counts recovered when HIV load was
suppressed and now back to early treatment in the most recent
WHO recommendations. As the exposure (HIV) cohort was
determined during or after 1999, it is probable that the majority
Gold J, et al. J Neurol Neurosurg Psychiatry 2014;0:1–4. doi:10.1136/jnnp-2014-307932

of patients would be taking highly active antiretroviral therapy
(HAART), which started to become widely used in the UK after
1995. At that time, the trend in clinical management of patients
with HIV was to recommend start of cART as early as possible18
and therefore it is likely that most of the exposed cohort were
taking antiretroviral therapies. This assumption is supported by
the global meta-analysis of temporal trends in CD4 cell counts
from 1992 to 2011 that determined the mean CD4 cell count
among HIV-positive patients in the UK was around 300 cells/
mL, which was during our period of observation, and this was a
level at which it is most likely cART would have been started.19
It is also probable that a number of patients were ﬁrst identiﬁed
as having HIV infection during the hospital admission when
they entered the HES cohort. In order to further test the
hypothesis that cART restricts the development of MS, we investigated the RR of MS cases in the exposed cohort relative to the
reference cohort 1 and 5 years, after the initial admission for
HIV or reference condition. These data revealed a further reduction in the RR from 0.38 (95% CI 0.15 to 0.79) overall, to
0.25 (95% CI 0.07 to 0.65; p<0.005) after 1 year, and 0.15
(95% CI<0.01 to 0.83; p=0.04) after 5 years. The overlapping
CIs of these point estimates mean that these differences are not
statistically signiﬁcant. However, if the progressive decline in
risk over time is real, a possible explanation is that during the
ﬁrst admission for HIV some patients were started on cART and
the effect of cART on the risk of MS did not begin until an
undetermined time period after discharge. Our data, indicating
the possible protective effect of cART increases at least 1 year
after the HIV indicator admission, may support this
observation.

Strengths and weaknesses
Strengths of our study are that it is national, in a population of
about 55 million and that we compared the exposed (HIV)
cohort with a large number of controls. The very large number
of controls per exposed person in each stratum (approximately
300:1), and the wide range of different control conditions,
would dilute any single factor that may bias the comparison of
the HIV and reference cohorts. The very large number of controls also allowed for precise calculation of the number of cases
of MS expected in the HIV cohort. Given that the hypothesis is
that there would be few cases of MS in the HIV cohort, precision in estimating the number of expected cases is particularly
important. Weaknesses of this type of study are numerous. Data
on ethnicity were sometimes missing. However, even though we
did not have ethnicity data for every participant we demonstrated that the deﬁcit appears not to be restricted to one ethnic
group. Our results are consistent with the pattern of ethnicity of
the HIV population in the UK, which is predominantly
Caucasian men. We have assumed that the time intervals
between the ﬁrst record of HIV and the ﬁrst record of MS, as
known to us, are generally reliable, but we have no way of
knowing this is absolutely certain.
We lack data on the proportion of the exposed population
who were actually taking cART and the exact combination of
drugs they may have been taking during the period of observation. We assume, from what is known about clinical practice
during the 12 years of data collection, that the majority of HIV
patients were probably either already on cART at the time of
entering the exposed cohort or were started on cART if HIV
was conﬁrmed at the time of the ﬁrst admission.
The ideal design for a study of the type reported would be a
randomised controlled intervention study where HIV-positive
patients are randomised to cART or no cART and followed to
3

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Multiple sclerosis
determine their risk of developing MS. Clearly, this study is
not feasible. Another option would be to try and investigate
what happened in the pre-cART time from 1981 when HIV was
ﬁrst described, until 1995, when cART was introduced.
Unfortunately, this is also not possible as there are no cohorts
large enough, in that era, to give a reasonable incidence of MS.
Moreover, there is always a possibility of misdiagnosis. HIV
infection may clinically present as MS-like symptoms with production of oligoclonal bands in cerebrospinal ﬂuid indistinguishable from MS. In the pre-cART era, with no
gadolinium-enhancing MRI available, patients with HIV who
presented with MS-like symptoms would generally have been
thought to have an HIV-related neurological condition rather
than diagnosed as having MS. HIV itself may cause various diseases of the white matter, in addition to an opportunistic infection, such as progressive multifocal leukoencephalopathy. If, in
reality, patients had MS, they would most likely have died
before the MS would become apparent. When cART became
available around 1995, any patients with HIV, presenting with
MS-like symptoms, would be assumed to have an HIV neurological condition and immediately started on cART. If MS were
the true underlying cause of their condition and their MS symptoms persisted even following cART, one would expect they
would be diagnosed with MS, while their HIV was controlled.
The unresolved question is that after almost 20 years of available cART, why do there seem to be almost no documented
cases of patients, in the literature so far, with coexisting MS and
HIV? Given that both MS and HIV result affect the immune
system, it is interesting to note that no pharmaceutical companies who produce therapies for either HIV or MS (no companies
produce therapies for both HIV and MS) have guidelines on
how to treat patients who have HIV and MS. In fact, medical
and marketing personnel at companies that produce MS disease
modifying treatments (DMTs) do not recall ever receiving an
inquiry about how to use these DMTs in patients with HIV who
are taking cART ( personal communication).

JG, RG, MG and DY developed the study design in consultation with the other
authors. RG, MG and DY conducted the data preparation and data analysis. JG, RG,
MG and HM wrote the ﬁrst draft of the manuscript to which all authors made
signiﬁcant subsequent contributions. GG provided practical guiding in-put to the
study as well as to the writing and review process.

Conclusion

10

This report is the largest record linkage study undertaken to
investigate a possible association between HIV and MS. Our
investigation revealed that having HIV, and presumptively being
on HAART, provided a signiﬁcant and potentially protective
effect in relation to the risk of development of MS. The magnitude of this effect (>60%) is at the highest level of any prognostic risk factor investigated to date. Nonetheless, there are
inevitable methodological uncertainties in our study design and
our ﬁndings should be regarded as speculative rather than
deﬁnitive. We have had to make reasonable assumptions about
the likelihood of our exposed HIV cohort being treated with
cART during the period of observation. Further consideration
may also be warranted on conducting other proof-of-concept
studies on using antiretroviral drugs in patients with different
types of MS. The ﬁrst clinical study with Raltegravir in patients
with relapsing remitting MS is already recruiting in the UK.20
Further investigation of our ﬁnding has the potential, after more
than 170 years since MS was ﬁrst described by Jean-Martin
Charcot, to help reveal the aetiology of MS.

Competing interests None.
Ethics approval Ethical approval for the construction and analysis of the linked
data set was granted by the Central and South Bristol Research Ethics Committee
(ref 04/Q2006/176).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Additional data can be generated from the HES
database if requested.
Open Access This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/3.0/

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Contributors All authors fulﬁl the authorship requirements and have approved the
ﬁnal version of the manuscript. JG, HM and GG developed the research question.

4

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Gold J, et al. J Neurol Neurosurg Psychiatry 2014;0:1–4. doi:10.1136/jnnp-2014-307932

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HIV and lower risk of multiple sclerosis:
beginning to unravel a mystery using a
record-linked database study
Julian Gold, Raph Goldacre, Hubert Maruszak, et al.
J Neurol Neurosurg Psychiatry published online August 4, 2014

doi: 10.1136/jnnp-2014-307932

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References

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Press releases (21 articles)
HIV/AIDS (96 articles)
Immunology (including allergy) (1656 articles)
Multiple sclerosis (797 articles)

Notes

Advance online articles have been peer reviewed, accepted for publication, edited and
typeset, but have not not yet appeared in the paper journal. Advance online articles are
citable and establish publication priority; they are indexed by PubMed from initial
publication. Citations to Advance online articles must include the digital object identifier
(DOIs) and date of initial publication.

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