APT Final Published Hiv Diarrhoea Revision
Transcript of APT Final Published Hiv Diarrhoea Revision
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See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/51509765
Review article: The aetiology, investigation andmanagement of diarrhoea in the HIV-positive
patient
ARTICLE in ALIMENTARY PHARMACOLOGY & THERAPEUTICS · SEPTEMBER 2011
Impact Factor: 5.73 · DOI: 10.1111/j.1365-2036.2011.04781.x · Source: PubMed
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3 AUTHORS:
Nicholas A Feasey
Liverpool School of Tropical Medicine
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Priya Healey
Royal Liverpool and Broadgreen University …
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Melita A Gordon
University of Liverpool
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http://www.researchgate.net/profile/Melita_Gordon?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_7http://www.researchgate.net/profile/Nicholas_Feasey?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_4http://www.researchgate.net/profile/Priya_Healey?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_4http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/publication/51509765_Review_article_The_aetiology_investigation_and_management_of_diarrhoea_in_the_HIV-positive_patient?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_3http://www.researchgate.net/?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_1http://www.researchgate.net/profile/Melita_Gordon?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_7http://www.researchgate.net/institution/University_of_Liverpool?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_6http://www.researchgate.net/profile/Melita_Gordon?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_5http://www.researchgate.net/profile/Melita_Gordon?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_4http://www.researchgate.net/profile/Priya_Healey?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_7http://www.researchgate.net/institution/Royal_Liverpool_and_Broadgreen_University_Hospitals_NHS_Trust?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_6http://www.researchgate.net/profile/Priya_Healey?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_5http://www.researchgate.net/profile/Priya_Healey?enrichId=rgreq-f96cd786-fe15-4902-a49b-be284d9131ef&enrichSource=Y292ZXJQYWdlOzUxNTA5NzY1O0FTOjEwMjAzNDc0OTUyNjAyN0AxNDAxMzM4Mzg4Nzg5&el=1_x_4http://www.researchgate.net/profile/Nichola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Review article: the aetiology, investigation and management of
diarrhoea in the HIV-positive patient
N. A. Feasey*,, P. Healey & M. A. Gordon*
*Department of Gastroenterology,
University of Liverpool, Liverpool, UK.
Malawi-Liverpool-Wellcome Trust
Major Overseas Programme, Blantyre,
Malawi.Department of Radiology, Royal Liv-
erpool University Hospital, Liverpool,
UK.
Correspondence to:Dr M. A. Gordon, University of Liver-
pool Gastroenterology Unit, Henry
Wellcome Laboratories, Nuffield Build-
ing, Crown Street, Liverpool L69 3GE,
UK.
E-mail: [email protected]
Publication data
Submitted 2 February 2011
First decision 23 March 2011
Resubmitted 28 June 2011
Accepted 30 June 2011
EV Pub Online 20 July 2011
This commissioned review article was
subject to full peer-review .
SUMMARY
Background
Diarrhoea is a common presentation throughout the course of HIV disease.
Aim
To review the literature relating to aetiology, investigation and management of
diarrhoea in the HIV-infected adult.
Methods
The PubMed database was searched using major subject headings ‘AIDS’ or ‘HIV’
and ‘diarrhoea’ or ‘intestinal parasite’. The search was limited to adults and to
studies with >10 patients.
Results
Diarrhoea affects 40–80% of HIV-infected adults untreated with antiretroviral ther-
apy (ART). First-line investigation is by stool microbiology. Reported yield varies
with geography and methodology. Molecular and immunological methods and spe-
cial stains have improved diagnostic yield. Endoscopy is diagnostic in 30–70% of
cases of pathogen-negative diarrhoea and evidence supports flexible sigmoidoscopy
as a first line screening procedure (80–95% sensitive for CMV colitis), followed by
colonoscopy and terminal ileoscopy. Radiology is useful to assess severity, distribu-
tion, complications and to diagnose HIV-related malignancies. Side effects and
compliance with ART are important considerations in assessment. There is a good
evidence base for many specific therapies, but optimal treatment of cryptosporidio-
sis is unclear and only limited data support symptomatic treatments.
Conclusions
The immunological response to HIV infection and antiretroviral therapy remains
incompletely understood. Antiretroviral therapy regimens need to be optimised to
suppress HIV while minimising side effects. Effective agents for management of
cryptosporidiosis are lacking. There is an urgent need for enhanced regional diag-nostic facilities in countries with a high prevalence of HIV. The ongoing roll-out
of antiretroviral therapy in low-resource settings will continue to change the aetiol-
ogy and management of this problem, necessitating ongoing surveillance and
study.
Aliment Pharmacol Ther 2011; 34: 587–603
ª 2011 Blackwell Publishing Ltd 587doi:10.1111/j.1365-2036.2011.04781.x
Alimentary Pharmacology and Therapeutics
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INTRODUCTION
Both acute and chronic diarrhoea have been recognised
as major complications of human immunodeficiency
virus (HIV) infection and the acquired immunodefi-
ciency syndrome (AIDS) since the early days of the pan-
demic, being described as ‘slim disease’ in Africa as a
result of the combination of watery diarrhoea and weight
loss that was characteristic.1 Definitions of chronic diar-
rhoea vary, but an accepted one is the abnormal passage
of three or more loose or liquid stools per day for more
than 4 weeks and ⁄ or a daily stool weight greater than
200 g ⁄ day.2 While acute bacterial gastroenteritis causes
blood stream invasion and death more frequently in
HIV-infected than in immune-competent patients,
chronic diarrhoea is also a massive problem for HIV
patients untreated with antiretroviral therapy (ART).
Case series from industrialised countries in the preanti-
retroviral (ARV) era (therefore involving untreated
patients) show that 40–80% of HIV-infected patients will
experience diarrhoea.3–5
Human immunodeficiency virus has an impact on
intestinal infection at all stages (by plasma CD4 count),
with additional aggregation of disease in individuals who
have increased susceptibility to diarrhoeal infection irre-
spective of CD4 count.6 While HIV associated diarrhoea
is most frequently caused by an opportunistic infection,
there are many non-infectious causes which should also
be considered. As the list of aetiological agents has
grown both with increased experience of HIV and as
powerful antiretroviral therapy (ART) has developed, sotoo has the array of investigations and therapeutics avail-
able to manage diarrhoea in HIV infection.
THE IMPACT OF HIV ON THE GASTROINTESTINAL
TRACT
The Human Immunodeficiency Virus (HIV) causes pro-
gressive immunosuppression as a consequence of its tro-
pism for CD4+ T-lymphocytes which progressively
decline because of apoptosis. Following acute infection,
there is a sharp initial fall in the plasma CD4 count,
which is followed by recovery and then a progressivedeterioration in the plasma CD4 count. Monitoring this
deterioration in plasma CD4 count is the major surro-
gate marker of immune status and is often the principal
tool in guiding the timing of initiation of ART. Plasma
CD4 T-lymphocyte count is, however, an imperfect mea-
sure of immune status for a number of reasons; one of
these is that the majority of CD4+ T-cells do not reside
in plasma, but in mucosal surfaces, particularly the gut,
where they form a major target for HIV in early infec-
tion prior to the development of a CD8+ T-cell response.
Furthermore, the immunosuppression seen in HIV is
extremely complex and consequent on the effects of HIV
viraemia on multiple branches of the immune system.
The mucosal surface of the gut is a unique interface
through which water and nutrients are absorbed during
digestion, where multiple commensal bacteria thrive and
which forms a structural and immunological barrier
against infection. It is not surprising that HIV infection
causes profound changes in the GI mucosa and its func-
tions, given the concentration of cells susceptible to HIV
infection found there, nor that the GI tract is conse-
quently a major reservoir for HIV and also a focus of
viral reproduction from the earliest days of infection.7–9
AETIOLOGY OF DIARRHOEA
The aetiology of diarrhoea in HIV-infected patients is
multi-factorial. Although opportunistic infections are an
obvious cause to consider, there are also many non-infectious causes of diarrhoea in HIV. There is a lack of
high quality prospective studies of the aetiology of diar-
rhoea in countries with the highest prevalence of HIV
and some of the early studies, although of high quality,
were constrained by both the limits of understanding of
the range of opportunistic infections and the diagnostic
technology available early in the HIV epidemic. Table 1
summarises studies of the aetiology of diarrhoea in HIV
and Figure 1 schematically represents potential causes of
diarrhoea in HIV by disease stage.
INFECTIONS
Different claims have been made about the relative
importance of bacteria, viruses and protozoan parasites
in the aetiology of infectious diarrhoea complicating HIV
in different studies. A number of factors have affected
the results of these studies, including the stage of HIV
infection, the range of diagnostic tests available at the
time of the study and the geographical location of the
study. It is important to note that opportunistic infec-
tions may still be found in patients who are taking anti-
retroviral therapy, partly because of poor adherence.10
Bacterial infection
Human immunodeficiency virus infected patients are at
risk of acute diarrhoea from the same bacterial agents of
enterocolitis as those who are HIV negative. They
are, however, at greater risk of prolonged infection
and of invasive disease, particularly from nontyphoid
Salmonellae11 and from Campylobacter jejuni.12, 13
Recurrent invasive nontyphoid Salmonella (NTS) disease
N. A. Feasey et al.
588 Aliment Pharmacol Ther 2011; 34: 587–603ª 2011 Blackwell Publishing Ltd
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T a b l e
1 | S u m m a r y o f s t u d i e s o
f a e t i o l o g y o f d i a r r h o e a i n H I V - i n f e c t
e d a d u l t s
S t u d y
S u b j e c t
L o c a t i o n
C o h o r t s i z e
T e c h n i q u e
M a j o r fi n d i n g s
S a k s i r i s a m p a n t e t a l . 1 3 1
I n t e s t i n a l p a r a s i t e s
T h a i l a n d
9 0 s t o o l s a m p l e s
M
i c r o s c o p y & P C R
4 6 % p o s i t i v e f o r
p a r a s i t e s , o f w h i c h : 3 0 %
C r . h o m
i n i s , 4 %
C r .
m e l e a g
r i d i s , 6 %
E .
b i e n e u s i 2 %
B . h o m i n i s ,
1 %
C .
c a y e t e n s i s , 1 %
I .
b e l l i
G o n c a l v e s e t a l . 1 3 2
C a u s e s o f d i a r r h o e a
c a s e c o n t r o l s t u d y
B r a z i l
4 0 p a t i e n t s w i t h
d i a r r h o e a , 6 0
w i t h o u t
M
i c r o s c o p y , c u l t u r e
E I A & P C R
C a l i c i v i r u s , C . p a r v u m
& G .
l a m b l i a s i g n i fi c a n t l y
a s s o c i a t e d w i t h d i a r r h o e a
D i l l i n g h a m
e t a l . 1 3 3
M o r t a l i t y : H I V
a s s o c i a t e d
d i a r r h o e a
H a i t i
2 8 8 p a t i e n t s
S t o o l m i c r o s c o p y
3 3 % h a
d a n e n t e r i c p a t h o g e n
i d e n t i fi e d : C r y p t o s p o r i d i u m
s p p . ,
G i a r d i a
s p p . , I . b e l l i , C . c a y e t a n e n -
s i s , a n d
E . h i s t o l y t i c a .
C h a c i n - B o n i l l a e t a l . 1 3 4
M i c r o s p o r i d i o s i s
V e n e z u e l a
1 0 3 p a t i e n t s
S t o o l m i c r o s c o p y
M i c r o s
p o r i d i a l i n f e c t i o n s
w e r e d e t e c t e d i n 1 4 %
a n d 3 8 %
h a d o t h e r
p a r a s i t i c p a t h o g e n s .
C h a c i n - B o n i l l a e t a l . 1 3 5
C y c l o s p o r a
c a y e t a n e n s i s
V e n e z u e l a
7 1 p a t i e n t s
S t o o l m i c r o s c o p y
C y c l o s p
o r a o o c y s t s w e r e
f o u n d
i n 1 0 %
B l a n s h a r d e t a l . 1 3 6
C h r o n i c d i a r r h o e a
U K
1 5 5 p a t i e n t s
E x a m i n a t i o n o f s t o o l s ,
d u o d e n a l , j e j u n a l
a n d r e c t a l b i o p s y
s p e c i m e n s a n d
d u o d e n a l a s p i r a t e
f o r b a c t e r i a l ,
p r o t o z o a l a n d v i r a l
p a t h o g e n s
8 3 % h a d 1 p a t h o g e n : s t o o l
a n a l y s
i s i d e n t i fi e d t h e
m o s t p a t h o g e n s ( 4 7 % ) .
R e c t a l b i o p s y n e c e s s a r y
f o r t h e d i a g n o s i s o f C M V
a n d a d e n o v i r u s . D u o d e n a l
b i o p s y
w a s a s h e l p f u l a s
j e j u n a l b i o p s y a n d
d e t e c t
e d s o m e t r e a t a b l e
p a t h o g e n s m i s s e d b y o t h e r
m e t h o
d s . E l e c t r o n
m i c r o s c o p y , i m p r e s s i o n
s m e a r
s a n d d u o d e n a l
a s p i r a t e y i e l d e d l i t t l e e x t r a
i n f o r m
a t i o n .
B l a n s h a r d a n d G a z z a r d
1 3 7
P a t h o g e n n e g a t i v e
d i a r r h o e a
U K
3 9 p a t i e n t s
F o l l o w - u p o f a b o v e
c o h o r t
2 s m a l l b o w e l n e o p l a s m , 3
C M V
Review: diarrhoea in HIV-positive patients
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has been considered an AIDS defining illness since
1985,14, 15 and advanced HIV-disease is associated with a
198–304-fold increased risk of invasive and multisite Sal-
monella infections.16 Diarrhoea may be a less prominentfeature of Salmonella infection in the setting of HIV.11
Campylobacter jejuni is another organism commonly
associated with diarrhoea in immunocompetent individu-
als which is an important cause of invasive disease and
morbidity and mortality in HIV-infected individuals. The
average incidence of Campylobacter among patients with
AIDS has been found to be 39 times higher than in non-
infected people,13 furthermore HIV-infected individuals
are much more likely to have debilitating disease requir-
ing prolonged courses of antimicrobials and in one series
the mortality of invasive disease was 33%.12
Otherspecies of this genus have also been implicated in diar-
rhoea in HIV. Other bacterial pathogens recognised to
cause diarrhoea more frequently in HIV-infected patients
include Escherichia coli, Shigella sp and Clostridium diffi-
cile. One study of trends in the aetiology of diarrhoea
proposed that C. difficile is the most common cause of
diarrhoea in HIV-infected adults in the US.17
Lymphogranuloma venereum (LGV), caused by sero-
vars L1–L3 of Chlamydia trachomatis, is endemic in
Africa and the Carribean, and was rare in industrialised
countries prior to 2003. It is currently re-emerging as a
sexually transmitted infection among men who have sex
with men (MSM), and HIV is a risk factor for suscepti-bility. WhilE genital LGV causes painful groin lymphade-
nopathy, gut mucosal infection can cause an ulcerative
rectocolitis, and adenopathy of the deep nodes which
drain the rectum may go unnoticed until they coalesce
to form a bubo, which may rupture and fistulate. The
clinical picture and histology may both mimic Crohn’s
disease and clinicians must be alert to the potential for
misdiagnosis and mistreatment in this setting. It is likely
that depletion of mucosal CD4 cells plays a critical role
is susceptibility to LGV in HIV.18, 19
Mycobacterial infection
The likelihood of developing extra-pulmonary and dis-
seminated infections with Mycobacterium tuberculosis
and nontuberculous mycobacteria increases as HIV-asso-
ciated immunosuppression progresses. Gastrointestinal
infection with numerous species of Mycobacteria may
occur in HIV. Both Mycobacterium tuberculosis and non-
tuberculous mycobacterial infection may present with
diarrhoea.20, 21 While diarrhoea is a relatively uncom-
0
200
400
600
800
1000
1200
1 000
10 000
100 000
1 000 000
Time since infection
10 years0–6 weeks
V i r a l l o a d ( c o p i e s / m L )
C D 4
c o un t
HIVsero-
conversion
Bacterial infectionTuberculosis
Isospora belli
Cyclospora cayatanensisStrongyloides
GI malignancies
ART side effects
CD4 count after commencing ARTCauses of diarrhoea related to ART
CD4 count without ART
Cryptosporidiamicrospor id ia MAC, CMV
Diarrhoea related to HIV se roconversion
Causes of diarrhoea as HIV disease progresses
Viral load without ART
Figure 1 | Scheme showing causes of diarrhoea at different stages of HIV disease: following HIV seroconversion, CD4
count recovers to a set point, then falls gradually over 5–0 years. The coloured boxes schematically indicate causes of
diarrhoea at different stages of HIV infection based on CD4+ T-lymphocyte count (blue line). The black dotted line
indicates the impact of starting ART on CD4 count and the overlap between different categories after starting ART
highlights the potential diagnostic difficulty at that time.
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mon symptom of tuberculosis, it is more commonly a
feature of disseminated infection with members of the
Mycobacterium avium complex (MAC). Disseminated
MAC infection occurs in advanced HIV and is frequently
associated with diarrhoea, which was reported to be
symptom in 17% of cases in one series.22
Parasitic infection
Numerous parasitic infections are known to cause diar-
rhoea in association with HIV. These include parasites
previously described to have pathogenic potential in HIV
negative patients (Giardia lamblia, Entamoeba histolytica,
Blastocystis hominis, Strongyloides stercoralis and other
soil transmitted helminths) and a number of parasites
either newly discovered or not previously thought to
have significant pathogenic potential, including Isospora
belli, Cryptosporidium parvum, Cyclospora cayetanensis,
and microsporidia particularly Enterocytozoon bienneusi
and Encephalocytozoon intestinalis. These organisms havesubsequently been identified as pathogens in otherwise
healthy people. The first three are intestinal spore form-
ing protozoa which cause intracellular infection and
which can lead to severe intestinal injury and prolonged
diarrhoea in advanced HIV,23 while microsporidia have
recently been reclassified as fungi. While some studies
have linked parasitic infection with progressive immuno-
suppression,24 others have questioned this association
and suggested that diarrhoeal infections aggregate in
HIV-infected individuals irrespective of CD4 count.6
Certainly risk factors for exposure to parasitic infection,particularly socio-economic status and access to safe
water and adequate sanitary facilities need to be consid-
ered when assessing an HIV-infected patient with
diarrhoea.
Viral infection
A number of viruses have been implicated in the aetiol-
ogy of diarrhoea in HIV-infected patients and the list
has grown and changed as advances have been made in
diagnostic virology. One of the first viral OIs to be listed
as an AIDS defining illness was Cytomegalovirus(CMV).25 CMV affects multiple organs in end stage HIV
and in the GIT can cause colitis. The hallmark is diar-
rhoea which may be bloody and accompanied by weight
loss, fever and abdominal pain. In early and pre-ART
cases series, CMV was a cause of approximately 15% of
HIV associated diarrhoea.26 The risk of CMV disease in
HIV is at its greatest as the CD4 count falls below
50 · 109 ⁄ L, consequently CMV related disease has rap-
idly declined with the roll out of ART.27 As with proto-
zoal OIs, the list of viral infections associated with
diarrhoea has grown substantially and now includes
astrovirus, picobirnavirus, caliciviruses (both norovius
and sapovirus) and adenoviruses.28 While these viruses
have been found significantly more frequently in the fae-
ces of patients with both HIV and diarrhoea than in that
of patients with HIV alone, causality has yet to be pro-
ven for all of them, particularly picobirnavirus.28 Diar-
rhoea is also a well documented feature of HIV
seroconversion illness itself.29, 30 This is important to
recognise as a combined antibody ⁄ antigen HIV test may
be negative during a seroconversion illness and if this
diagnosis is suspected, the HIV test should be repeated
12 weeks after the initial test.
Fungi
Candida species are frequently isolated from the stool of
HIV-infected patients31 and have been implicated in
antibiotic associated diarrhoea;32 however, their role inthe aetiology of diarrhoea remains unclear and further
studies are needed into the role of yeasts in HIV-associ-
ated diarrhoea. Systemic dimorphic fungal infection can
affect the gastrointestinal tract causing diarrhoea, for
example disseminated infection with Histoplasmosis.33
PATHOGEN-NEGATIVE DIARRHOEA
The concept of ‘pathogen-negative diarrhoea’ has evolved
as the understanding of the breadth of OIs which cause
diarrhoea has evolved. One study of patients classified as
having pathogen-negative diarrhoea on entry to thestudy observed that in the majority of the more severe
cases, an infectious cause was ultimately identified,34 fur-
thermore this study preceded the first reports of intesti-
nal microsporidiosis as a cause of diarrhoea in HIV.35
The hunt for novel infectious causes of enteropathy in
HIV-infected patients continues.
The role of HIV itself
Despite this, it is clear that there are changes in the bowel
attributable to HIV disease itself, which have important
functional significance. Massive and progressive depletionof gastrointestinal effector memory CD4+ T lymphocytes
is seen early in the course of HIV disease, and the simian
model disease SIV.36 The suggested mechanisms are direct
infection of cells and bystander cell death. One of the most
important consequences of this loss of gut mucosal CD4
cells is a failure to maintain the epithelial barrier function
of the gut mucosa.37 This mucosal damage enables micro-
bial products to translocate across the bowel. LPS levels in
both HIV and SIV have been found to be elevated and are
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temporarily reduced following neomycin treatment.38
Translocated microbial products such as LPS, peptidogly-
can and viral genomes may cause chronic gastrointestinal
and systemic immune activation through stimulation of
the innate immune system via Toll-like receptors. The
resultant activated T-cells in turn are a further target for
HIV, thus driving a vicious circle in the immunopathogen-
esis of HIV disease.39, 40 The impact of HIV infection of
the gut mucosa may therefore extend to influence overall
progression of the disease systemically. These changes,
however, also have significant functional consequences for
the gut itself and also may be linked to the longstanding
observations that there is a jejunal enteropathy termed
‘HIV enteropathy’, associated with mild villous atrophy
and crypt hyperplasia.41–43 Increased permeability and
decreased absorption for sugars, vitamin B12 and bile have
been described, even in the absence of detectable opportu-
nistic infections, associated with chronic diarrhoea and
malnutrition in HIV.44–48 A third subset of T-lymphocyteshas recently been discovered and characterised, which act
through IL-17 to coordinate gut mucosal protection
against infection. The loss of the TH17 subset of CD4 cells
from the gut mucosa is thought to be particularly impor-
tant during HIV49 and in addition to the consequences for
HIV disease progression described above, the loss of IL-
17-producing T cells has been shown to permit invasion
and dissemination of nontyphoidal Salmonella from the
gut in an SIV model.50
Another suggested mechanism for HIV-related diar-
rhoea has been rapid intestinal transit due to damage tothe autonomic nervous system; HIV is known to be neu-
rotropic and a generalised autonomic neuropathy in
advanced HIV is well described.51 Increased transit time,
however, does not correlate well with symptomatic diar-
rhoea.45 HIV-associated inflammatory bowel disease,
which has been defined as ‘a non-infectious colitis refrac-
tory to standard treatment for inflammatory bowel dis-
ease’ is characterised by colitis52 or caecitis (typhlitis)53
and may also cause pathogen-negative diarrhoea.
HIV-associated malignancyHuman immunodeficiency virus-associated gastrointesti-
nal malignancies may also present with pathogen-negative
diarrhoea.4 Non-Hodgkin B-cell lymphoma and Kaposi
sarcoma are both AIDS-defining and are considered non-
infectious, although their pathogenesis is ultimately related
to oncogenic herpes viruses such as EBV and HHV8.
Non-Hodgkin lymphomas (NHL) are 60–200-fold
increased among HIV-infected patients, commonly EBV-
related, and the categories most likely to affect the GI tract
are Burkitt and Burkitt-like lymphomas54, 55 and diffuse
large B-cell lymphomas (DLBCL), which frequently pres-
ent with extra-nodal involvement including of the GI tract,
reflected by a predominance of gastrointestinal symptoms
including diarrhoea.56 Primary effusion lymphoma (PEL)
is known to be HIV-related and an extracavitary, solid var-
iant has recently been described which commonly affects
the gastrointestinal tract and is HHV8-associated, with fre-
quent EBV co-infection.57
Hodgkin lymphoma is also 10-fold over-represented in
HIV, although it is not AIDS-defining and its incidence
in HIV has a nonlinear relationship with CD4 count and
disease stage.58 Cases present with advanced disease, ex-
tranodal disease and ‘B’ symptoms, but not typically with
diarrhoea or luminal GI disease.57 The importance of the
GI-related non-AIDS defining malignancies Hodgkin
Lymphoma and anal carcinoma is increasing with the
advent of HAART as patients are living longer.
Kaposi sarcoma, caused by HHV8, is AIDS-defining and is a multifocal disease which very frequently involves
the GI sub-mucosa. While GI involvement is often
asymptomatic, Kaposi’s may present with diarrhoea,59, 60
GI bleeding (since it is a very vascular tumour), perfora-
tion, intussusception or obstruction.
Pancreatic disease
Human immunodeficiency virus infection may have mul-
tiple effects impairing exocrine pancreatic action, which
in turn may contribute to chronic diarrhoea through
impaired fat absorption. Factors associated with pancre-atic disease include OIs, viral hepatits, HIV itself and
ART,61 although the principal culprit, didanosine, is
rarely used now. One study found measurement of faecal
elastase to assess pancreatic exocrine insufficiency to
enable treatment with oral pancreatic enzyme therapy to
be useful in the management of chronic diarrhoea.62
Antiretroviral therapy as a cause of diarrhoea
In 1987, Zidovudine (AZT) became the first pharmaco-
logical agent with proven efficacy against HIV.63 In the
late 1990s, combination ART became the standard of care to combat the rapid emergence of drug-resistance
and it has been so successful that patients diagnosed
early in the course of HIV infection can expect a near
normal lifespan.64 Multiple classes of ARVs are now
available; however, these agents are not without side
effect and diarrhoea is a common consequence of ART
which may be severe enough to lead to discontinuation
of ARVs.65 While diarrhoea has been associated with all
three main classes of ARVs; nucleoside reverse transcrip-
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tase inhibitors (NRTIs), non-nucleoside reverse transcrip-
tase inhibitors (NNRTIs) and protease inhibitors (PIs),
perhaps the most problematic agents are the PIs, particu-
larly ritonavir,66 which is used to boost levels of other
PIs.67 The dosage of ritonavir and dosing schedules of
PIs is a subject of major interest.68
INVESTIGATION
An algorithmic approach to investigation and manage-
ment of chronic diarrhoea in HIV is shown in Figure 2.
To guide management, an accurate history concerning
the patient’s HIV, their treatment history and their pro-
fessional and recreational exposure to pathogens and their
travel history should be sought. All of the pathogens listed
are transmitted by the faecal-oral route and are all poten-
tially sexually transmitted. This information is equally
important for clinicians and medical scientists consider-
ing which tests to perform. Additional features of the his-
tory and examination may help distinguish between small
or large-bowel diarrhoea, and the possibility of complica-
tions. Although molecular diagnostics are predicted to
enhance the sensitivity of investigations in the future, the
majority of first-line clinical diagnostic tests routinely
available are still based on microscopy and culture.
Microbiological investigation
Upon making a diagnosis of HIV, the most basic investi-
gations necessary are a plasma CD4 count and HIV viral
load (see Figure 2). The CD4 count will help to assess
the degree of immunosuppression and thus clarify the
spectrum of OIs to which the patient susceptible. The
viral load is the most useful parameter of response to
ARVs and in early treatment failure will increase before
the CD4 count starts to decline.
Initial clinical assessment including:
Severity
Drug history
CD4 count and HIV Viral Load
Stool examination:
3 samples over 10 different days
Microscopy for ova, cysts & parasites
(ZN stain, trichrome stain)
Bacterial culture
C. difficile screen
Specific virology and protozoal PCR
Supportive management
Antimotility agents, adsorbents, cholestyramine,
octreotide, etc
Start or optimise ARVs to:control VL, minimise drug side effect
Review all other drugs, withdraw suspect drugs
Flexible sigmoidoscopy:
Biopsies for histology, standard and mycobacterial
culture and CMV PCR
Pathogen negative diarrhoea?
Colonoscopy with terminal ileoscopy
(or consider gastroscopy)Cross sectional imaging (malignancy, disease extent,
complications, tissue biopsy)
consider : double contrast upper GI barium study
consider : complete TB diagnostic work-up
Specific treatment for:
Additional infectious agents identified
HIV-associated malignancies
Mycobacterial disease
Empirical or specific treatment for:
Infectious agents
Figure 2 | Algorithm showing the management approach to the HIV patient with diarrhoea.
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Investigation of faeces
Microbiological investigation of faeces should be the first
investigation of diarrhoea. Different specimens provide
different challenges to a diagnostic microbiology labora-
tory; faecal culture is made challenging by the difficulty
of ensuring that the pathogen or pathogens among a
diverse array of bacteria is identified. A faecal sample
should be collected and submitted soon as possible after
the onset of symptoms. While a 1–2 g specimen is suffi-
cient for routine culture, more is required for the array
of tests which may be necessary in the context of HIV
and diarrhoea. Specimens of faeces should be transported
to the laboratory and processed as soon as possible,
because a number of important pathogens such as Shi-
gella species may not survive the pH changes that occur
in faeces specimens which are not promptly delivered to
the laboratory, even if refrigerated.69 Three samples over
no more than a 10 day period are recommended for
detection of parasites, although more may be necessary,especially if Giardia is suspected. No more than one
specimen per day should be submitted as shedding of
ova and cysts tends to be intermittent.70
Once received by a diagnostic laboratory, specimen
processing depends on the clinical context, but should
include culture on a media which favours selection of
Salmonella sp and Shigella sp and a second which selects
for Campylobacter sp. Consideration should be given to
testing for Clostridium difficile toxins A and B. Recovery
of mycobacteria from stool is uncommon therefore
mycobacterial stool culture is not recommended.69
Stool should be examined using direct microscopy for
the ova and cysts of protozoal parasites; however, a screen
for Cryptosporidia, Cyclospora, Isospora and microsporidia
requires a specific request as these organisms require spe-
cific stains. A modified acid fast stain is used to look for
the oocysts of cryptosporidia, isospora and cyclospora,
although the sensitivity is unknown and operator depen-
dant. Examining multiple specimens increases sensitiv-
ity.23 Diagnosis of microsporidia is also challenging, in
part because their size (1–2 lm) makes them difficult to
differentiate from faecal debris by light microscopy.71
Improved methods include microscopy following staining
with modified trichrome stain72 with or without a chemo-
fluorescence brightener such as calcoflour white; however,
the gold standard test remains transmission electron
microscopy (TEM) on small bowel biopsy specimens.
Other methods include antigen and antibody based detec-
tion methods and nucleic acid amplification techniques.71
Nucleic acid amplification tests are increasingly used
in the diagnosis of sexually acquired infection. Since
2005 several such tests have become available for the
diagnosis of LGV from anal swabs. The clinician must
consider the diagnosis of LGV to make the diagnosis.
Virology
Diagnosis of the viral infections which cause diarrhoea is
complex and species specific. While TEM (performed on
tissue) and viral culture enable the identification of new
viruses and viruses not expected in a given clinical con-
text (i.e. non-enteric adenoviruses causing diarrhoea in
HIV positive patients), the skills required for these tech-
niques are rarely used outside of reference laboratories.
Increasingly, viral infections are diagnosed using
enzyme-immunoassay (EIA), latex agglutination kits or
polymerase chain reaction (PCR) performed on stool,
blood or tissue. In the context of CMV, assays for CMV
DNA or antigen in blood are superior to culture for doc-
umenting viraemia73 and few UK laboratories use CMV
culture. Further prospective studies are required to deter-mine whether PCR of blood or tissue is the most sensi-
tive assay for diagnosing intestinal CMV,74 however
histology gives the best indication of disease severity.
The rapid reduction in the cost of whole genome
sequencing may make mass sequencing a viable diagnos-
tic option in the near future. This approach will also
enable the discovery of novel viruses.
Other microbiology
In addition to stool samples, blood should be taken for
culture from febrile or septic patients and considerationshould be given to mycobacterial blood culture. If TB is
suspected, alternative microbiological specimens should
be sought including mucosal biopsy, lymph node tissue
or ascites for histology and culture, combined with
radiological evidence of TB, including a chest X-Ray in
all patients (http://www.nice.org.uk/CG033NICEguide-
line). The role of rapid PCR-based diagnostic tests for
TB is likely to expand. Blood for specific serology, anti-
gen testing or PCR may be useful; however, patients with
advanced HIV may lose the ability to mount an antibody
response to the point where serology is negative.
Endoscopy
There has been much debate about the usefulness or
necessity for pan-endoscopy to investigate stool-
negative diarrhoea in HIV. Not all studies are directly
comparable, since sensitivity clearly depends not only
on the extent of examination, but on the associated
microbiological methods used for both stool and
biopsy material, which have improved over time. Geo-
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graphical location, disease stage, the underlying risk
factor for HIV and the advent of HAART may also
be confounders in these studies. Endoscopy yields an
additional diagnosis in 30–70% of stool-negative cases,
depending on methods and the completeness of study.
Unsurprisingly, diagnostic yield is highest when there
are worse symptoms, and at lower CD4 count. The
commonest additional or new diagnoses uncovered by
endoscopy are CMV colitis, microsporidiosis and giar-
dia infection. There is a general consensus that 85–
90% of cases of CMV colitis will be detected using
flexible sigmoidoscopy and biopsy alone4, 34, 75–77 and
flexible sigmoidoscopy is generally considered a neces-
sary and adequate first-line assessment in stool-negative
diarrhoea. There are, however, a smaller number of
studies suggesting that proximally distributed CMV
colitis or other colonic diagnoses may be missed and
full colonoscopy (preferably with terminal ileoscopy) is
warranted if severe or functionally debilitating symp-toms persist.26, 78 Although some studies have sug-
gested that biopsy of the small bowel, either at
duodenoscopy or terminal ileoscopy, is necessary to
reliably diagnose microsporidiosis,76 improved microbi-
ological stool methods such as PCR or trichrome stain
mean that the necessity for small bowel biopsy is now
reduced. The high pick-up rate for microsporidiosis in
the terminal ileum, combined with the detection of
proximally distributed CMV colitis, means that colo-
noscopy with terminal ileoscopy is a logical second-line
investigation and may obviate the need for upper GIendoscopy. The decreasing utility of upper GI endos-
copy to diagnose pathogens in HIV is confirmed in
other recent studies.79
Radiology
Radiology of opportunistic infections and inflammatory
disease. Interpretation of diagnostic imaging of the
HIV-infected patient presenting with diarrhoea can be
challenging as the appearances are usually nonspecific.80
The most common findings in infectious diarrhoea are
of oedematous and ulcerated mucosa. The distributionand type of ulcers and the extent of disease when corre-
lated with the degree of immunosupression can aid in
narrowing the wide differential diagnosis of the various
infectious pathogens, but endoscopic samples need to be
obtained for histopathological or microbiological investi-
gation to make a definitive diagnosis.81, 82
Literature on the appearances of the bowel in patients
with diarrhoea and HIV is sparse. Imaging of mucosal
detail, such as the pattern and distribution of ulcers and
oedema, is best seen in barium studies. Mucosal detail is
not apparent on CT or MRI and the appearances of the
bowel are not pathogen specific. CT or MRI scanning is
undertaken in patients with more severe disease to assess
disease distribution, potential complications, for staging
tumours and to aid intervention. If these modalities are
unavailable, ultrasound may demonstrate small and large
bowel thickening.83
While a tissue or microbiological diagnosis must be
sought, imaging can suggest certain diagnoses. Tubercu-
losis commonly affects the ileocaecal region resulting in
mural thickening of the terminal ileum and caecum. Skip
areas in the small bowel may mimic Crohn’s disease with
luminal narrowing and proximal dilatation, but the pres-
ence of skip lesions with ileocaecal involvement is
strongly suggestive of TB. Necrotic mesenteric lymphade-
nopathy can be seen on CT and is also suggestive of TB
infection.84 Advanced disease results in the classic
appearance of a conical small caecum. Colonic involve-ment results in segmental ulcers, strictures and polypoid
hypertrophic lesions.
Mycobacterium avium affects the jejunum with thick-
ening of the folds, but there is no ulcer as MAI is not
associated with tissue destruction. Normal appearances
are seen in 25% of infected patients undergoing CT.85
Cytomegalovirus infection most commonly affects the
colon and radiological appearances vary depending on
the severity. Bowel wall thickening, ulcers and irregular
folds are seen on barium studies and CT. With increas-
ing severity of disease, large ulcers, nodular defects andpseudo-membranes may develop. Tumour like lesions
may develop which may be indistinguishable from neo-
plasia.86 Thrombosis secondary to vasculitis with subse-
quent ischaemia may result in penetrating ulcers and
subsequent perforation.87 Histoplasmosis also affects the
colon, particularly the ascending colon. The thickening
of the bowel and pericolonic inflammatory change can
mimic carcinoma.88
Human immunodeficiency virus-related typhlitis (cae-
citis) is localised inflammation of the caecum with sym-
metric wall thickening, pneumatosis and pericolonicinflammation. This can extend to involve the terminal
ileum and ascending colon.89 Diagnosis takes account of
and is based on the entire clinical picture, rather than by
imaging alone. CT imaging is particularly useful to
exclude a perforation or abscess and to guide
intervention.90
Radiology of neoplastic lesions. The lesions of Kaposi
sarcoma are submucosal in location and can affect any
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part of the gastrointestinal tract, most commonly the
duodenum. Barium studies in the early stages may be
negative as the lesions are submucosal and diagnosis
may be more readily achieved endoscopically. When
advanced, both barium studies and CT may demonstrate
larger flat or polypoid submucosal masses with or with-
out ulcers and associated fold thickening. Enhancing
lymph nodes are seen commonly in patients with dis-
seminated disease which may aid diagnosis. Otherwise,
the lesions may mimic other neoplastic lesions such as
carcinoma, metastases or lymphoma or infections.91
Acquired immunodeficiency syndrome-related non-
Hodgkins lymphoma (NHL) in HIV has been found to
affect extra-nodal sites in 86% of abdominal CT scans,
the commonest being the GI tract.92 Primary B-cell lym-
phoma in HIV patients often affects the distal small
bowel. Thickening of the distal ileum, mass like lesions,
ulcers and aneurysmal dilatation may be seen on CT with
extension of tumour into the adjacent mesentery andlymph nodes. Barium studies are nonspecific demonstrat-
ing polypoid mass lesions, ulcers and infiltrative change
or nodularity. Intussusception and bowel obstruction may
occur and the appearances may be indistinguishable from
carcinoma.93 The patterns and distribution of intestinal
findings on CT imaging of small bowel NHL are not dis-
tinguishable from those seen in HIV-uninfected cases.94
Other investigations
A diagnosis of Mycobacterium tuberculosis (MTB) com-
plex can be inferred from a localised immune reaction tointradermal injection of Mycobacterial purified protein
derivative (PPD, the tuberculin test). More sophisticated
ex-vivo tests based on detection of interferon gamma
release in response to two antigens specific to MTB (and
which are not found in the BCG vaccine) have recently
been introduced. Interferon gamma release assays (IGRAs)
may be more sensitive than intradermal PPD in HIV-
infected adults.95 More work needs to be carried out to
define the role of IGRAs in the diagnosis of extrapulmo-
nary TB in HIV-infected adults and no studies have
focused on the use of IGRAs in intestinal tuberculosis.Despite this, a positive tuberculin-test or IGRA may be of
value in supporting a diagnosis of MTB,96 while a negative
result should be interpreted with caution.
MANAGEMENT AND OUTCOMES
Treatment of infectious diarrhoea by aetiology
The first steps in managing diarrhoea in the context of
HIV are the same as those taken in managing any acute
diarrhoea; to evaluate which pathogens the patient is at
risk of by taking a careful history and to assess and man-
age dehydration, although known HIV infection should
lower the threshold for using antimicrobial therapy.
There is increasing, but geographically heterogeneous
resistance to multiple antimicrobials among enteric
pathogens, making recommendation of an empirical
antimicrobial unrealistic, instead expert local advice
should be sought or local guidelines consulted in the
management of the critically ill patient. Ultimately, iden-
tification of specific organisms by culture will enable
antimicrobial susceptibility testing to be performed.
Lymphogranuloma venereum proctocolitis caused by
Chlamydia trachomatis requires a prolonged course of
therapy. Either doxycycline or a macrolide is recom-
mended, although there are no clinical trials to guide the
use of macrolides. There is also interest in fluoroquinol-
ones, although again, trial data are lacking.
Mycobacterial infection
Gastrointestinal infection with M. tuberculosis is treated
in the same fashion as pulmonary tuberculosis, initially
using a four drug regimen involving rifampicin, isonia-
zid, pyrazinamide and ethambutol dosed according to
patient weight for 2 months followed by a further
4 months of rifampicin and isoniazid.97 Following cul-
ture of M. tuberculosis, sensitivity testing should be per-
formed to refine the antituberculous regimen if
resistance is detected. Treatment of MAI consists of a
macrolide, rifamycin and ethambutol given three timesweekly for noncavitary disease and daily with or without
an aminoglycoside for cavitary disease.98 Antimycobacte-
rial therapy for MAI should not be stopped until
immune reconstitution with ART has occurred.99
Protozoal and fungal infections
Despite a drive to diagnose HIV earlier and the introduc-
tion of ART, protozoal infections continue to cause diar-
rhoeal disease in HIV-infected patients and they frequently
present a therapeutic challenge. The drugs of choice for
Giardiasis are metronidazole (2 g ⁄ day for 3 days) or tini-dazole (2 g once), with a cure rate of 73–100%.100 Nitazox-
anide is an alternative with an 81% success rate. 101 There
are inadequate and conflicting trials of specific therapy
for cryptosporidiosis with both nitazoxanide and
paroromycin. A recent Cochrane meta-analysis of seven
trials including 130 adults with HIV concluded that
although nitaxozanide reduces the load of parasites and
may be useful in immunocompetent individuals, the effect
was not significant for HIV-infected patients. Despite this,
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the use of nitaxozanide should be considered in very sick
HIV-infected patients with Cryptosporidiosis.102 Trials of
paroromycin have included even fewer HIV-infected
patients and the same meta-analysis found no statistically
significant effect. Further trials are unquestionably war-
ranted; however, the mainstay of treatment is effective
immune reconstitution with ART.103–105
The treatment of Isoporiasis and Cyclospora is more
straightforward. Both pathogens are susceptible to co-
trimoxazole, which may resolve symptoms in up to
100% of patients.106 In the case of intolerance or allergy
to sulphonamides, ciprofloxacin may be used, although it
is less effective, resolving only 87% cases.106
The main specific therapy for microsporidiosis is alben-
dazole. While Encephalitozoon intestinalis responds well to
albendazole 400 mg b.d. for 3 weeks, which caused clinical
resolution and parasite clearance in 4 ⁄ 4 patients in one
study,107 Enterocytozoon bieneusi does not. Albendazole
should still be tried, but supportive therapy with fluids andearly initiation of ART are crucial. As with cryptosporidio-
sis, immune reconstitution can lead to complete clearance
of microsporidia.103
Anti-viral therapy
Specific anti-viral therapy is available for CMV colitis
using IV ganciclovir or oral valganciclovir. Alternatively
foscarnet and cidofovir have been approved, but there
are no clinical trials to support a specific therapy for
CMV colitis. Immune reconstitution is an essential com-
ponent of treating CMV disease.
Prophylactic therapy
Cotrimoxazole remains a useful prophylactic agent in
HIV-infected patients. While in the developed world, it is
primarily used to prophylax against PCP and toxoplasma
encephalitis in the profoundly immunosuppressed (plasma
CD4 count less than 200 · 109 ⁄ L), it will also prevent isos-
pora diarrhoea.108 Cotrimoxazole is used much earlier in
the course of HIV in developing countries (plasma CD4
count less than 500 · 109 ⁄ L). This is in part due to its
prophylactic role against malaria, but it also prevents diar-rhoea.109
Secondary prophylaxis is recommended by the CDC
for the prevention of recurrent nontyphoid Salmonella
sepsis, but not for other enteric bacterial pathogens.108
Antiretroviral therapy
The treatment of HIV was revolutionised initially by the
introduction of Zidovudine ⁄ AZT and subsequently by
combination ART. Now multiple classes of ARVs are
available and what was once a terminal illness should
now be regarded as a chronic, treatable medical disorder.
Current regimens for ARV naive patients are well toler-
ated with low pill burdens. In the early days of HIV
therapy, the consensus was that treatment was unneces-
sary until the CD4 count fell to around 200 · 109 ⁄ L.
This decision was based on the perceived risk of OIs at
CD4 counts of 200–400 · 109 ⁄ L or less, the severe side
effects of early regimens and the cost of ART. Current
guidelines recommend that ART should start before the
CD4 count falls below 350 · 109 ⁄ L,110 with many experts
advocating even earlier treatment,111 although this
remains controversial.
Antiretroviral therapy rapidly reduces plasma HIV
viral load enabling the CD4+ T-lymphocyte population
to reconstitute and there is good evidence that this
reduces chronic diarrhoea in HIV-infected individuals,
often very rapidly.112 Sampling of gut tissue reveals a
rapid fall in viral load,112 which suggest that the virushas a central role in HIV-associated diarrhoea. There is
robust evidence of both a general reduction in gastroin-
testinal OIs113 with the introduction of ART and of
improvement in the outcome from infection with specific
OIs. Infections caused by pathogens which have no spe-
cific treatment may resolve following the introduction of
ART including cryptosporidiosis and microsporidiosis,103
while the treatment of other OIs for which specific ther-
apy is available (i.e. CMV colitis) is enhanced by the
introduction of ART.27 Lastly, recurrence of invasive bac-
terial infections such as Salmonellosis has been shown tocease following introduction of ART.114
Despite the clinical improvement that is frequently
seen, the picture at a GI cellular level is more complex.
The completeness of gastrointestinal reconstitution is
controversial with some studies showing good CD4 T-
cell repletion, while others have suggested that it is both
poor and much slower than the improvement in plasma
CD4 count40 and that in the long term, patients with
poor GI CD4 reconstitution have ongoing immune acti-
vation. One possible explanation for this is the
observation that some GI CD4 cells have been observedto produce HIV years after initiation of ART.115, 116 A
second possibility is that fibrotic damage to GI lymphoid
tissue prior to initiation of ART may be such that the
ability to replace CD4 T-cells in the GIT is permanently
impaired40 and early initiation of ART certainly fosters a
more complete CD4 reconstitution in the GIT.115, 116
Although gut mucosal CD4 depletion does not com-
pletely reconstitute following antiretroviral therapy, pos-
sibly because of the deposition of collagen in GALT,117
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many of the functional consequences, including perme-
ability defects, are measurably reversed.118
Symptomatic treatment of chronic diarrhoea
Chronic diarrhoea in Western populations is now
increasingly rare due to the introduction of ART early in
the course of HIV infection. Despite exhaustive investiga-
tion of diarrhoea and initiation of ART, diarrhoea may
persist or even result from HIV therapy and empirical
treatment may be required. Antimotility agents (lopera-
mide, diphenoxylate and codeine) and adsorbents (bis-
muth subsalicylate, kaolin ⁄ pectin and attapulgite) have
anecdotally been found to be useful. Antimotility agents
increase gut transit time, giving more time for fluid reab-
sorption and while narcotic analgesics should be avoided
because of their addictive nature, loperamide and di-
phenoxylate may be useful, although studies are lacking.
A recent Cochrane review highlighted the lack of evi-
dence for these agents and the need for further stud-ies.119 Cholestyramine may be beneficial if diarrhoea is
caused by malabsorption of bile salts.120 Other measures
studied include zinc or other micronutrient supplementa-
tion, mesalazine (mesalamine) and curcumin. Rando-
mised controlled trials of zinc supplementation121 and
mesalazine122 in adults revealed no benefit, while a small
study of the turmeric extract curcumin revealed a benefit
in five of six patients.123 A Cochrane review has con-
cluded that micronutrient supplementation offers no
reduction in morbidity (including diarrhoea) or mortality
among HIV-infected adults.124 One more recent study of broader micronutrient supplementation did not result in
significant reduction in diarrhoea, although there was a
very modest reduction in severe infectious diarrhoea.125
Supplementation with vitamin A and zinc, however, has
failed to significantly reduce gut permeability or markers
of microbial translocation.126 Although octreotide has
been used for symptomatic control of diarrhoea in HIV
enteropathy, the results of trials are inconsistent.127–129
In the case of HIV-related colitis, thalidomide has been
used with success in individual patients,52 but randomised
controlled trials are lacking. Typhlitis or caecitis has beensuccessfully managed with bowel rest, IV fluids and broad
spectrum antibiotics.130 Discussion of chemotherapy for
mitotic lesions is beyond the scope of this review, but the
expert opinion of an oncologist should be sought in
the case of discovery of an HIV-related malignancy as the
cause of diarrhoea and it should be remembered that tight
control of HIV viraemia forms an essential part of the
treatment of these cancers.
CONCLUSIONS
Human immunodeficiency virus infection impacts upon
the gastrointestinal tract in a variety of ways and there is
an incomplete understanding of the mechanisms by which
it does this. The aetiology of diarrhoea in HIV infection is
diverse and includes the direct effects of the virus upon the
GIT, infection with both obligate and opportunistic ente-
ropathogens, malignant and other ‘non-infectious’ causes
and as a consequence of anti-viral therapy. In addition,
HIV-infected patients are still susceptible to unrelated but
common causes of diarrhoea including irritable bowel dis-
ease and drug side effects. A multidisciplinary approach to
diagnosis and management is therefore best practice and
in the best interests of the patient.
Faecal microbiology remains the principal and first-
line investigation for diarrhoea in HIV-infected patients.
Tests typically available routinely include microscopy,
culture and enzyme immunoassays. In recent years, the
cost of genome sequencing technology has plummeted
and its increasing availability is revolutionising microbi-
ology. Failure to detect pathogens by currently available
diagnostic microbiology may lead to a need for complex
radiology or the judicious use of endoscopy and tissue
biopsy.
Flexible sigmoidoscopy is generally acknowledged to
be an appropriate first-line investigation in stool-negative
cases, and full colonoscopy with visualisation and biopsy
of the terminal ileum, rather than gastroduodenoscopy is
generally a reasonable second-line endoscopic investiga-
tion. Radiological findings are often nonspecific but use-ful to detect disease severity, distribution and
complications, and some HIV-related malignancies.
While current research suggests that people diagnosed
with HIV infection today might expect to live a normal
life if adherent to their therapy, ARVs may themselves
cause diarrhoea and further research is needed to opti-
mise drug dosage, particularly with protease inhibitors. A
good evidence-base for symptomatic management of
HIV-related diarrhoea is also lacking. The greatest bur-
den of HIV infection falls on Sub-Saharan African coun-
tries where there are limited diagnostic facilities.National and regional prevalence studies of enteropatho-
gens are needed, both to inform regional and national
treatment strategies and to highlight the true burden of
disease attributable to neglected or newly discovered
pathogens. The intestinal parasites also number among
the neglected tropical diseases and new therapies for
these pathogens are urgently needed for both HIV-
infected and uninfected patients.
Review: diarrhoea in HIV-positive patients
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ACKNOWLEDGEMENTS
Declaration of personal interests: None. Declaration of
funding interests: No financial support was received for
the preparation of this manuscript. Dr Feasey is supported
by a Wellcome Trust Research Training Fellowship.
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