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For peer review only
Prevalence and incidence of pulmonary arterial hypertension among HIV-infected adolescents and adults in
Africa: a systematic review and meta-analysis
Journal: BMJ Open
Manuscript ID bmjopen-2016-011921
Article Type: Research
Date Submitted by the Author: 15-Mar-2016
Complete List of Authors: Bigna, Jean Joel; Centre Pasteur of Cameroon, Epidemiology and Public Health; University of Bordeaux, Bordeaux School of Public Health Nansseu, Jobert Richie; Mother and Child Centre, Chantal Biya Foundation, Sickle cell unit; Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Department of Public Health Um, Lewis; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Noumegni, Steve Raoul; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Simé, Sandra Paule; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Noubiap, Jean Jacques; Groote Schuur Hospital and University of Cape Town, Department of Medicine Koulla-Shiro, Sinata; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences; Yaoundé Central Hospital, Infectious Diseases Unit
<b>Primary Subject Heading</b>:
Respiratory medicine
Secondary Subject Heading: Epidemiology, HIV/AIDS, Public health
Keywords: pulmonary arterial hypertension, pulmonary hypertension, HIV & AIDS < INFECTIOUS DISEASES, Africa
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Prevalence and incidence of pulmonary arterial hypertension among HIV-
infected adolescents and adults in Africa: a systematic review and meta-
analysis
Jean Joel R. Bigna1, 2*
Jobert Richie N. Nansseu3, 4
Lewis N. Um5 ([email protected])
Steve Raoul N. Noumegni5 ([email protected])
Paule Sandra D. Simé5 ([email protected])
Jean Jacques N. Noubiap6, 7
Sinata Koulla-Shiro5, 8
1Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé,
Cameroon 2Bordeaux School of Public Health, University of Bordeaux, Bordeaux, France
3Department of Public Health, Faculty of Medicine and Biomedical Sciences, University of
Yaoundé 1, Yaoundé, Cameroon 4Sickle Cell Disease Unit, Mother and Child Centre of the Chantal Biya Foundation,
Yaoundé, Cameroon 5Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé,
Cameroon 6Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape
Town, South Africa
7Medical Diagnosis Center, Yaoundé, Cameroon
8Infectious Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon
* Correspondence to: Dr Jean Joel R. Bigna, Department of Epidemiology and Public Health,
Centre Pasteur of Cameroon, PO Box 1274, Yaoundé, Cameroon; Email:
Keywords
Pulmonary arterial hypertension; pulmonary hypertension; HIV; AIDS, Africa
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Abstract
Objective: Patients infected with HIV have a direly increased risk of developing pulmonary
arterial hypertension (PAH), and of dying from the condition. While Africa carries the
greatest burden of HIV infection worldwide, there is unclear data summarizing the
epidemiology of HIV-related PAH. The objective was to determine the prevalence and
incidence of HIV-related PAH in African adolescents and adults living across Africa.
Design: A systematic review and meta-analysis.
Participants: African HIV-infected adults and adolescents residing in Africa.
Outcome: Prevalence and incidence of PAH diagnosed through echocardiography or right
heart catheterization.
Data sources: Articles published in PubMed/Medline between 1st January 1980 and 31
st
January 2016, without any language restriction.
Results
Overall, 5 studies were included in this review: 3 from Southern Africa (Tanzania, Zimbabwe
and South Africa), one from Central Africa (Cameroon), and one from Western Africa
(Nigeria). There was no study from Eastern or Northern Africa. No study reported HIV-
induced PAH incidence. The definition of PAH was not homogenous across studies, and
quality assessment yielded low to moderate risk of bias. Ages of participants ranged between
10-78 years, and the proportion of females varied between 52.3%-71%. The cut-off to define
PAH was not identical across studies: a pulmonary arterial systolic pressure (PASP) ≥ 25
mmHg vs. ≥ 35 mmHg. The prevalence of PAH in the pooled sample of 980 patients was
11.3% (95% CI, 5.6%–21.3%).
Limitations: Only one database was screened, and there were only 5 studies found eligible.
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Conclusion: The prevalence of HIV-induced PAH in Africa is very high. Health care
providers should regularly screen their HIV-infected patients for PAH throughout the
continent.
Funding: No particular funding needed.
Registration: PROSPERO CRD42016033863
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Strengths and limitations
• Only one database was screened, and only 5 studies were eligible.
• It was impossible to disaggregate data between patients on antiretroviral treatment and
those naïve for antiretroviral treatment.
• This is first meta-analysis summarizing prevalence of pulmonary arterial hypertension
among HIV-infected people in Africa.
• This systematic review and meta-analysis shows a higher relative prevalence of HIV-
related pulmonary arterial hypertension in Africa.
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Introduction
HIV continues to be a major global public health issue, having hampered more than 34
million lives so far. There were approximately 36.9 million people living with HIV at the end
of 2014, with 2.0 million people becoming newly infected worldwide; what’s worse, 1.2
million people died from HIV-related consequences in 2014. Sub-Saharan Africa (SSA) is
the most affected region with 25.8 million people living with HIV in 2014. Besides, SSA
accounts for almost 70% of the global HIV new infections 1 2
.
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) ≥ 25
mmHg on right heart catheterization at rest 3. The classification of PH includes: pulmonary
arterial hypertension (PAH), PH due to left heart diseases, PH due to respiratory diseases
and/or hypoxemia, PH due to chronic embolic disease, and PH having unclear multifactorial
mechanisms 3. PAH is defined by the combination of a mPAP ≥ 25 mmHg, a pulmonary
capillary wedge pressure ≤ 15 mmHg, and a pulmonary vascular resistance > 3 Wood units at
the time of right heart catheterization 3. To date, evidence has accumulated a causal
relationship between the HIV infection and PAH 4. The pathogenesis of PAH is complex.
From what is known, this may probably result from the interaction between multiple
modulating genes and environmental factors. The physiopathology includes: (i) cytokines
secretion increase which induces a dysregulation of endothelial and vascular smooth muscle
cell growth and an imbalance between endogenous vasodilators and constrictors; (ii) HIV
viral proteins proliferation which induces vascular oxidative stress, smooth myocyte
proliferation and migration, and endothelial injury; and (iii) genetic predisposition due to
some major histocompatibility complex alleles, particularly HDL-DR6 and HLA-DR5 4.
HIV-infected patients have a greater incidence of PAH and almost a 2500-fold increased risk
of developing the condition, in comparison with the general population (incidence of
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idiopathic PAH: 1-2 per million persons) 5 6
. Furthermore, the development of PAH in HIV
infected individuals reduces the probability of survival by half in these patients as compared
with their counterparts without HIV-induced PAH. About two thirds of deaths in patients
with HIV-induced PAH are due to the consequences of PAH such as: right heart failure,
cardiogenic shock, and sudden death 7.
While Africa carries the highest burden of HIV infection globally 1 2
, there is unclear data
summarizing the epidemiology of PAH in HIV-infected populations. We therefore planned to
conduct a systematic-review and meta-analysis, the objective of which was to determine the
prevalence and incidence of HIV-induced PAH in African adolescents and adults residing
inside Africa.
Methods
The preferred reporting items for systematic reviews and meta-analyses guidelines served as
the template for conducting and reporting the present review 8. The preferred reporting items
for systematic reviews and meta-analyses checklist can be found in S1 Appendix. This review
is registered in the PROSPERO International Prospective Register of systematic reviews,
registration number CRD42016033863.
Eligibility criteria for considering studies to include in the review
Inclusion criteria
- Cross-sectional, case-control or cohort studies of HIV-infected adult participants residing
in African countries which have reported the prevalence or incidence of HIV-induced
PAH, or enough data to compute these estimates.
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- Studies in which diagnosis of PAH was based on echocardiography or right heart
catheterization.
We considered all published and unpublished studies reported from 1st January 1980 to 31
st
January 2016. No language restriction was applied.
Exclusion criteria
- Studies conducted among populations of African origin residing outside Africa.
- Studies not performed in human subjects.
- Studies in subgroups of participants selected on the basis of the presence of PAH.
- Case series (sample size less than 30 subjects), reviews, letters, commentaries and
editorials.
- Studies lacking primary data and/or explicit method description.
For duplicate reports, the most comprehensive and up-to-date version was considered for this
review
Search strategy for identifying relevant studies
The search strategy was implemented in two stages:
Bibliographic database search
We performed a comprehensive and exhaustive search of PubMed/Medline to identify all
relevant articles published on HIV-induced PAH in Africa between 1st January 1980 and 31
st
January 2016, without any language restriction. We conceived and applied a search strategy
based on the combination of relevant terms and names of each of the 54 African countries
and African sub-regions. We used the following terms for PAH: “pulmonary hypertension”
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and “pulmonary arterial hypertension”. For HIV, we used the terms “HIV” and “AIDS”. The
last electronic search was run on February 1st, 2016. The search strategy is shown in S2
Appendix.
Searching other sources
We conducted manual searches which consisted in scanning the reference lists of eligible
papers and other relevant review articles, specialist journals and conference proceedings.
Selection of studies for inclusion in the review
Two investigators (JJRB and LNU) independently identified articles and sequentially
screened their titles and abstracts for eligibility. Full texts of articles deemed potentially
eligible were acquired. These investigators further independently assessed the full text of
each study for eligibility, and consensually retained studies to be included. Disagreements
when existing were solved by a third author (JRNN). We used a screening guide to ensure
that the selection criteria were reliably applied by all reviewers.
Data extraction and management
Two reviewers (JJRB and LNU) independently extracted data pertaining to general
information (authors, year, country, region), study characteristics (study design, setting,
sample size, mean or median age and proportion of female participants, diagnosis criteria for
PAH, antiretroviral therapy), prevalence and/or incidence of PAH. Where only primary data
(sample size and number of outcomes) were provided, these data were used to calculate the
prevalence or incidence estimates. Data were extracted using a preconceived and
standardized data abstraction form. Disagreements between authors were reconciled through
discussion and consensus, or arbitration by a third author (JRNN) whenever necessary.
Appraisal of the quality of included studies
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We evaluated included studies for methodological quality and risk of bias using an adapted
version of the Risk of Bias Tool for Prevalence Studies developed by Hoy et al (Appendix
S3).9 Furthermore, the reporting quality of each study was assessed using the STROBE
checklist (Appendix S4) 10
.
Data synthesis and analysis
Data were analyzed using the Comprehensive Meta-Analysis software, Version 2 (Biosta,
Inc. USA). Forest plots were drawn to visualize the combined prevalence and extent of
heterogeneity of studies. Heterogeneity was assessed using the χ2 test on Cochrane’s Q
statistic 11
, and quantified by calculating the I2 (with values of 25 %, 50 % and 75 % being
representative of low, medium and high heterogeneity respectively) 12
. When I2 statistic was
less than 50% and the p-value for the test of heterogeneity was ≥ 0.1, studies were
considered homogenous and a fixed effects meta-analysis was used to estimate the overall
prevalence. Otherwise, a random effects meta-analysis was used 13
. When heterogeneity was
present, subgroup analyses were used to explore the potential reasons for heterogeneity.
These subgroup analyses were performed using the following grouping variables: age group,
sex, geographical region (Central, Southern, Western, Northern, and Eastern Africa),
patients’ clinical presentation, and study quality. In order to assess possible publication bias,
Egger weighted regression methods were used 14
. A p-value < 0.05 was considered indicative
of statistically significant publication bias.
Results
Characteristics of included studies
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Initially, a total of 26 articles were identified (Fig 1). After screening the titles and abstracts,
18 papers were found completely irrelevant; therefore they were excluded. Then, the full-
texts of the remaining 8 studies were scrutinized for eligibility, among which three studies
were excluded: one study did not include participants on the basis of their HIV status 15
; one
study was a duplicate report 16
, and the diagnosis of pulmonary hypertension was solely
based on clinical assessment in the third study 17
. Overall, five studies were found eligible,
hence were included in this review (Fig 1).
Figure 1. Process of identification and selection of studies for inclusion in the review
(PRISMA flow diagram).
All the 5 studies reported the prevalence of HIV-induced PAH without any analysis with
regard to the patients’ ART regimens; none reported the incidence of the condition. The
studies were reported from Tanzania, Zimbabwe, Nigeria, Cameroon and South Africa; there
was no study from the Eastern or Northern parts of Africa. They were conducted between
2006 and 2014, and were published between 2012 and 2015. The characteristics of these five
studies are summarized in Table 1. Chillo et al. 18
, Menanga et al. 19
, and Sliwa et al. 20
reported studies in which patients were selected based on presentation with cardiovascular
complaints while Ferrand et al. 21
and Isiguzo et al. 22
reported studies in which patients were
asymptomatic. Diagnosis criteria for PAH were not identical across studies: three studies
defined PAH with a pulmonary arterial systolic pressure (PASP) ≥ 25 mmHg 20-22
, and the
two others, with a PASP ≥ 35 mmHg 18 19
. One of the studies was reported among adolescents
(range between 10 and 19 years) 21
, and the others among adults (mean age varying between
39 and 48.5 years).18-20 22
. The female proportion in studies varied from 52.3% to 71% (Table
1).
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Table 1. Characteristics of studies included in the meta-analysis 1
First
author
Study
period
Year of
publicati
on
Study
design
Countries Geograph
ical
region
Patient
presentation
Diagnosis
criterion of
PAHa
Duration on
ARTb
Mean age
(range),
years
Number of
female (%)
Chillo 18 2009-2010 2012 Cross
sectional
Tanzania Southern
Africa
Selected based on
cardiovascular
complaints
PASP ≥ 35
mmHg
Not reported 42.4 (18-72) 70 (68.6%)
Ferrand 21 Not
reported
2012 Cross
sectional
Zimbabwe Southern
Africa
Asymptomatic PASP ≥ 25
mmHg
Median 20
months
14 (10-19) 80 (69.0%)
Isiguzo 22 2010 2013 Cross
sectional
Nigeria Western
Africa
Asymptomatic PASP ≥ 25
mmHg
Not reported 39 (18-
above)
142 (71%)
Menanga 19
2014 2015 Cross
sectional
Cameroon Central
Africa
Selected based on
cardiovascular
complaints
PASP ≥ 35
mmHg
Mean 37,3
months
48.5 (42-72) 23 (52.3%)
Sliwa 20 2006-2008 2012 Cross
sectional
South
Africa
Southern
Africa
Selected based on
cardiovascular
complaints
PASP ≥ 25
mmHg
Not reported 40 (18-72) 321 (62%)
PASP: pulmonary arterial systolic pressure; ART: antiretroviral therapy 2
aPulmonary arterial hypertension diagnosis used echocardiographic Doppler 3
bAll studies included patients on antiretroviral therapy and those who were not; the duration is obviously for patients on ART 4
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Considering STROBE guidelines, the quality of reporting was good/fair for all included 1
studies. These studies had a low to moderate risk of bias (Table 2). 2
Table 2. Quality assessment of included studies 3
STROBE quality of reporting* Risk of bias by Hol et al. £
Score range, 0
to 22
Interpretation Score range,
0 to 10
Interpretation
Chillo, 2012 18 17 Good/fair
quality
7 Moderate risk
Ferrand, 2012 21
17 Good/fair
quality
9 Low risk
Isiguzo, 2013 22 17 Good/fair
quality
10 Low risk
Menanga, 2015 19
19 Good/fair
quality
7 Moderate risk
Sliwa, 2012 20
19 Good/fair
quality
6 Moderate risk
*A quality assessment score out of 22 was determined for each study by assigning a point per 4
STROBE item addressed. Good/fair quality papers was categorized as having a score of ≥ 5
14/22 and poor quality papers will be classified as having a score of <14/22 10
. 6
£ Low risk of bias: 8 or more. Moderate risk of bias: 6 to 7. High risk of bias: 5 or fewer
9. 7
8
Pooled prevalence of pulmonary arterial hypertension among HIV-infected people in 9
Africa 10
There was a wide variation in PAH prevalence (Fig 2). The heterogeneity was high (I2
= 11
90.0%, p < 0.001); therefore a random effect model was used to pool rates of the five studies. 12
The prevalence of PAH in the pooled sample of 980 individuals was 11.3% (95% CI, 5.6%–13
21.3%). Some evidence for publication bias was observed (Fig 3); however the results of 14
Egger’s weighted regression test did not show bias of publication (t = 0.208, p = 0.424). 15
Figure 2. Forest plots of HIV-related pulmonary arterial hypertension prevalence among 16
HIV-infected people in Africa. 17
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Figure 3. Funnel plots of standard errors of HIV-related pulmonary arterial hypertension 1
prevalence among HIV-infected people in Africa. 2
Subgroup and sensitivity analyses 3
Regarding results of Egger’s weighted regression test, there was no publication bias for all 4
subgroup and sensitivity analyses. Looking at their 95% confidence interval, the prevalence 5
of PAH was the same between males and females, between studies with sample size < 200 6
and ≥ 200 participants, between adolescents and adults, and between patients presenting with 7
cardiovascular complaints and those asymptomatic at presentation. The prevalence was 8
different with respect to the diagnosis criteria for PAH: 24.1% (95%CI 17.9-31.8%) when the 9
definition criterion was a PASP ≥ 35 mmHg, and 7.2% (95%CI 5.6-9.2%) with PASP ≥ 25 10
mmHg as the cut-off to define PAH. Moreover, the prevalence of PAH was higher in Central 11
Africa than in Western Africa: 29.5% (95%CI 18.0-44.5%) vs. 4.0% (95%CI 2.0-7.8%) 12
respectively. There was neither a difference between Central Africa and Southern Africa nor 13
between Southern Africa and Western Africa (Table 3). 14
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Table 3. Subgroup prevalence of HIV-related pulmonary arterial hypertension 1
Subgroup Number
of studies
n/N Prevalence, % 95% confidence
interval
Heterogeneity
test, I² (p value)
Egger’s test, t
(p value)
Sex group
• Female 2 35/462 5.7 1.7-17.8 82.9% (0.016) NP
• Male 2 15/256 5.9 3.6-9.5 0 (0.703) NP
Sample size
• Sample size < 200 3 43/262 17.3 7.8-34.1 85.1% (0.001) 0.57 (0.335)
• Sample size ≥ 200 2 50/718 6.1 3.1-11.8 72.3% (0.058) NP
Age group
• Adolescents (10-19 years) 1 8/116 6.9 3.5-13.2 - -
• Adults (18 and above) 4 85/864 12.6 5.6-26.1 92.1% (<0.001) 0.42 (0.359)
Diagnosis criteria
• PASP ≥ 35 mmHg 2 35/146 24.1 17.9-31.8 6.1% (0.302) NP
• PASP ≥ 25 mmHg 3 58/834 7.2 5.6-9.2 44.8% (0.163) 1.33 (0.205)
Geographical region
• Central Africa 1 13/44 29.5 18.0-44.5 -
• Southern Africa 3 72/736 11.0 5.2-21.7 88.4 (<0.001) 0.208 (0.435)
• Western Africa 1 8/200 4.0 2.0-7.8 - -
Patients’ clinical presentation
• Asymptomatic 2 16/316 5.2 3.2-8.4 20.1 (0.263) NP
• Cardiovascular complaints 3 77/664 17.4 7.3-36.0 92.6 (<0.001) 3.71 (0.08)
Risk of bias
• Low 2 16/316 5.2 3.2-8.4 20.1 (0.263) NP
• Moderate 3 77/664 17.4 7.3-36.0 92.6 (<0.001) 3.71 (0.08)
NP: Not possible (It is necessary to have at least three studies to compute) 2
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Discussion 1
These moderate to low risk of bias studies conducted between 2006 and 2014 from three 2
WHO regions of Africa showed a pooled 11.3% prevalence of PAH among HIV African 3
infected adolescents and adults. The prevalence of PAH among HIV-infected people in 4
Africa found in this meta-analysis is included in the range (5-13%) reported in a recent 5
narrative review targeting the same population 4. This prevalence in sub-Saharan Africa is 6
notably higher when compared to that reported for developed countries, which is around 7
0.5% 6 23-25
. Certain reasons can explain this large discrepancy observed. Indeed, access and 8
retention in care are lower in low- and middle-income countries (including most of African 9
countries) leading to late diagnosis and management of HIV infection. Consequently, patients 10
will probably arrive at a more advanced stage of disease progression. Besides, ART initiation 11
in developed countries does not take into consideration the CD4 count and HIV clinical stage 12
by contrast to the developing world where these parameters are taken into account, leading to 13
initiation of ART perhaps when HIV-induced complications such as PAH have already 14
started developing 26-29
. 15
Two subgroup analyses explained the high heterogeneity (I2
= 90.0%) found for our pooled 16
prevalence. Surprisingly, the meta-analysis of studies using diagnosis criteria of PAH with 17
PASP ≥ 35 mmHg reported a higher prevalence than that with PASP ≥ 25 mmHg. This may 18
be explained by the fact that of the three studies with the cut-off to define PAH at PASP ≥ 35 19
mmHg, two of them included patients with cardiac complaints. We can note a non-significant 20
difference between prevalence among HIV asymptomatic patients (5.2%) and HIV patients 21
with cardiac complaints (17.4%). The prevalence of PAH was also higher in Central Africa 22
(29.5%) compared to Western Africa (4.0%). It can be worth noticing that the study 23
conducted in Central Africa included HIV patients with cardiac complaints 19
; in fact, they 24
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can be at increased risk of having PAH compared to asymptomatic HIV patients who were 1
included in the study from Western Africa 22
. Nevertheless, this finding should be interpreted 2
with caution, since the comparison was done only between two studies, one of which 3
included not more than 44 patients 19
. 4
For now, there is no cure for pulmonary arterial hypertension 30
. Nonetheless, the use of 5
highly active antiretroviral therapy (HAART), whose aim is to prevent the multiplication of 6
HIV and thus make undetectable the viral load; could reduce the risk of development or 7
progression of PAH in patients infected with HIV. It has been demonstrated indeed that the 8
detection of plasma HIV-RNA was associated with the risk to develop PAH 23
. This suggests 9
also that early initiation of HAART may prevent or delay PAH apparition in HIV infected 10
individuals. However, HAART should not be used as a sole therapy for HIV-induced PAH; 11
early initiation of PAH-specific management is of paramount importance. In fact, HAART 12
only ameliorates the outcome of patients with HIV-induced PAH 4. 13
14
Limitations 15
Unfortunately, our study presents some flaws. First, our study was based on a limited number 16
of published studies. Nonetheless, it included all studies found in PubMed/Medline which is 17
the greatest database for biomedical resources. Second, concerning quality of evidence, risk 18
of bias of included studies was low to moderate suggesting that further research is likely to 19
have an important impact on our confidence in the estimate, and may change this estimate. 20
Moreover, none of the studies included in this review assessed the incidence of HIV-induced 21
PAH as well as the relation between the condition and antiretroviral therapy (ART) 22
(difference between ART+ and ART- patients, the specific regimens increasing the risk, the 23
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duration of ART at which PAH is likely to occur). Therefore, high-quality observational 1
studies are warranted to fill these crucial gaps. 2
3
Conclusions 4
This study has shown that more than one African HIV infected adolescent/adult on ten 5
(11.3%) has PAH, which is high, and may direly contribute in the elevated HIV-related 6
mortality rate witnessed all-round Africa. Therefore, health care providers must be aware of 7
this reality, and undertake regular screening of their HIV infected patients with regard to 8
PAH, and those diagnosed with the condition, be properly and efficiently managed. Besides, 9
it should be discussed early initiation of HAART in African countries to curtail the burden of 10
HIV-induced PAH as well as other HIV-related complications. New 2015 World Health 11
Organization guidelines on initiation of ART regardless CD4 count, age, HIV disease 12
progression will be welcome. Further studies are urgently warranted, which should determine 13
the incidence of HIV-induced PAH, and the relation between PAH and ART in African HIV 14
infected individuals. 15
16
17
Authors’ contributions 18
Study conception and design: JJRB. Study selection: JJRB and LNU. Data extraction: JJRB 19
and LNU. Statistical analysis: JJRB. Data interpretation: JJRB and JRNN. Drafting: JJRB. 20
Manuscript reviewing and revision: JJRB, JRNN, LNU, SRNN, PSDS, JJNN, SK-S. All 21
authors approved the final version to publish. 22
23
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Funding 1
This research received no specific grant from any funding agency in the public, commercial 2
or not-for-profit sectors. 3
4
Competing interests 5
We have read and understood BMJ policy on declaration of interests and declare that we have 6
no competing interests. 7
8
Data sharing statement 9
No additional data are available. 10
11
References 12
1. World Health Organization. HIV/AIDS: Fact sheet N°360. Secondary HIV/AIDS: Fact 13
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http://www.unaids.org/sites/default/files/media_asset/20150714_FS_MDG6_Report_16
en.pdf. 17
3. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary 18
hypertension. Journal of the American College of Cardiology 2013;62(25 19
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4. Bigna JJ, Sime PS, Koulla-Shiro S. HIV related pulmonary arterial hypertension: 21
epidemiology in Africa, physiopathology, and role of antiretroviral treatment. AIDS 22
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5. Correale M, Palmiotti GA, Lo Storto MM, et al. HIV-associated pulmonary arterial 24
hypertension: from bedside to the future. European journal of clinical investigation 25
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6. Crothers K, Huang L, Goulet JL, et al. HIV infection and risk for incident pulmonary 1
diseases in the combination antiretroviral therapy era. American journal of respiratory 2
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A case control study. Swiss HIV Cohort Study. American journal of respiratory and 5
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8. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 7
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9. Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: modification 9
of an existing tool and evidence of interrater agreement. Journal of clinical 10
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11. Cochran GW. The Combination of Estimates from Different Experiments. Biometrics 15
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12. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in 17
medicine 2002;21(11):1539-58. 18
13. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. 19
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14. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, 21
graphical test. BMJ 1997;315(7109):629-34. 22
15. Makubi A, Hage C, Lwakatare J, et al. Contemporary aetiology, clinical characteristics 23
and prognosis of adults with heart failure observed in a tertiary hospital in Tanzania: 24
the prospective Tanzania Heart Failure (TaHeF) study. Heart 2014;100(16):1235-41. 25
16. Bakari M, Chillo P, Lwakatare J. Factors associated with, and echocardiographic findings 26
of heart failure among HIV infected patients at a tertiary health care facility in Dar es 27
Salaam, Tanzania. Tanzania journal of health research 2013;15(2):73-81. 28
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Pathol Exot 2002;95(1):23-6. 31
18. Chillo P, Bakari M, Lwakatare J. Echocardiographic diagnoses in HIV-infected patients 32
presenting with cardiac symptoms at Muhimbili National Hospital in Dar es Salaam, 33
Tanzania. Cardiovascular journal of Africa 2012;23(2):90-7. 34
19. Menanga AP, Ngomseu CK, Jingi AM, et al. Patterns of cardiovascular disease in a group 35
of HIV-infected adults in Yaounde, Cameroon. Cardiovasc Diagn Ther 36
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20. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency 1
virus/acquired immunodeficiency syndrome epidemic to de novo presentations of 2
heart disease in the Heart of Soweto Study cohort. European heart journal 3
2012;33(7):866-74. 4
21. Ferrand RA, Desai SR, Hopkins C, et al. Chronic lung disease in adolescents with 5
delayed diagnosis of vertically acquired HIV infection. Clinical infectious diseases : 6
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52. 8
22. Isiguzo GC, Okeahialam BN, Danbauchi SS, et al. Contributions of pulmonary 9
hypertension to HIV-related cardiac dysfunction. Indian heart journal 2013;65(5):644-10
9. 11
23. Quezada M, Martin-Carbonero L, Soriano V, et al. Prevalence and risk factors associated 12
with pulmonary hypertension in HIV-infected patients on regular follow-up. AIDS 13
2012;26(11):1387-92. 14
24. Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. 15
Chest 1991;100(5):1268-71. 16
25. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary 17
arterial hypertension in the current antiretroviral therapy era. American journal of 18
respiratory and critical care medicine 2008;177(1):108-13. 19
26. Kassaye SG, Katzenstein D. HIV/AIDS care and treatment in sub-Saharan Africa. AIDS 20
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27. Giuliano M, Vella S. Inequalities in health: access to treatment for HIV/AIDS. Annali 22
dell'Istituto superiore di sanita 2007;43(4):313-6. 23
28. Shors AR. The global epidemiology of HIV/AIDS. Dermatologic clinics 2006;24(4):413-24
20, v. 25
29. Cleary S. Equity and efficiency in scaling up access to HIV-related interventions in 26
resource-limited settings. Current opinion in HIV and AIDS 2010;5(3):210-4. 27
30. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 28
2004;351(16):1655-65. 29
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S1 Appendix. PRISMA checklist.
Section/topic # Checklist item Reported on page #
TITLE 1
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT 2-3
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2-3
INTRODUCTION 5-6
Rationale 3 Describe the rationale for the review in the context of what is already known. 5-6
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
6
METHODS 6-9
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
6
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 6-7
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
7-8
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
8
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 8
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
8
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
8
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Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
9
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 9
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency
(e.g., I2) for each meta-analysis.
9
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
9
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
9
RESULTS 9-14
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
10
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
10
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 11
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
11-14
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 11
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 10
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 13
DISCUSSION 14-18
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
15
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
16
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 15-16
FUNDING 16
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Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
17
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S2 Appendix. Pubmed/Medline search strategy for studies published between January
1st, 1986 and January 31
th, 2016
Search Search terms Hits
#1 "Pulmonary hypertension" OR "Pulmonary arterial hypertension" 34 722
#2 “HIV” OR “AIDS” 372 684
#3 (Africa OR Algeria OR Angola OR Benin OR Botswana OR
"Burkina Faso" OR Burundi OR Cameroon OR "Canary Islands" OR
"Cape Verde" OR "Central African Republic" OR Chad OR
Comoros OR Congo OR "Democratic Republic of Congo" OR
Djibouti OR Egypt OR "Equatorial Guinea" OR Eritrea OR Ethiopia
OR Gabon OR Gambia OR Ghana OR Guinea OR "Guinea Bissau"
OR "Ivory Coast" OR "Cote d'Ivoire" OR Jamahiriya OR Kenya OR
Lesotho OR Liberia OR Libya OR Madagascar OR Malawi OR Mali
OR Mauritania OR Mauritius OR Mayotte OR Morocco OR
Mozambique OR Namibia OR Niger OR Nigeria OR Principe OR
Reunion OR Rwanda OR "Sao Tome" OR Senegal OR Seychelles
OR "Sierra Leone" OR Somalia OR "South Africa" OR "St Helena"
OR Sudan OR Swaziland OR Tanzania OR Togo OR Tunisia OR
Uganda OR "Western Sahara" OR Zaire OR Zambia OR Zimbabwe
OR "Central Africa" OR "Central African" OR "West Africa" OR
"West African" OR "Western Africa" OR "Western African" OR
"East Africa" OR "East African" OR "Eastern Africa" OR "Eastern
African" OR "North Africa" OR "North African" OR "Northern
Africa" OR "Northern African" OR "South African" OR "Southern
Africa" OR "Southern African" OR "sub Saharan Africa" OR "sub
Saharan African" OR "subSaharan Africa" OR "subSaharan
African") NOT ("guinea pig" OR "guinea pigs" OR "aspergillus
niger")
348 009
#4 #1 AND #2 AND #3 26
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S3 Appendix. Risk of bias assessment tool, adapted from the Risk of Bias Tool for
Prevalence Studies developed by Hoy et al.
Risk of Bias Item Answer:
Yes (Low Risk) or No
(High risk)
External Validity
1. Was the study target population a close representation of
the general HIV population in relation to relevant variables?
2. Was the sampling frame a true or close representation of the
target population?
3. Was some form of random selection used to select the
sample, OR, was a census undertaken?
4. Was the likelihood of non-participation bias minimal?
Internal Validity
5. Were data collected directly from the subjects (as opposed
to medical records)?
6. Were acceptable case definition of pulmonary arterial
hypertension used?
7. Was a reliable and accepted diagnosis method pulmonary
arterial hypertension utilized?
8. Was the same mode of data collection used for all subjects?
9. Was the length of the shortest prevalence period for the
parameter of interest appropriate?
10. Were the numerator(s) and denominator(s) for the
calculation of the prevalence of pulmonary arterial
hypertension appropriate?
Summary item on the overall risk of study bias
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Appendix S4. STROBE Statement: checklist of items that should be included in reports
of observational studies
Item
No Recommendation
Title and abstract 1 (a) Indicate the study’s design with a commonly used term
in the title or the abstract
(b) Provide in the abstract an informative and balanced
summary of what was done and what was found
Introduction
Background/rationale 2 Explain the scientific background and rationale for the
investigation being reported
Objectives 3 State specific objectives, including any prespecified
hypotheses
Methods
Study design 4 Present key elements of study design early in the paper
Setting 5 Describe the setting, locations, and relevant dates, including
periods of recruitment, exposure, follow-up, and data
collection
Participants 6 (a) Cohort study—Give the eligibility criteria, and the
sources and methods of selection of participants. Describe
methods of follow-up
Case-control study—Give the eligibility criteria, and the
sources and methods of case ascertainment and control
selection. Give the rationale for the choice of cases and
controls
Cross-sectional study—Give the eligibility criteria, and the
sources and methods of selection of participants
(b) Cohort study—For matched studies, give matching
criteria and number of exposed and unexposed
Case-control study—For matched studies, give matching
criteria and the number of controls per case
Variables 7 Clearly define all outcomes, exposures, predictors, potential
confounders, and effect modifiers. Give diagnostic criteria, if
applicable
Data sources/
measurement
8* For each variable of interest, give sources of data and details
of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than
one group
Bias 9 Describe any efforts to address potential sources of bias
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Study size 10 Explain how the study size was arrived at
Quantitative variables 11 Explain how quantitative variables were handled in the
analyses. If applicable, describe which groupings were
chosen and why
Statistical methods 12 (a) Describe all statistical methods, including those used to
control for confounding
(b) Describe any methods used to examine subgroups and
interactions
(c) Explain how missing data were addressed
(d) Cohort study—If applicable, explain how loss to follow-
up was addressed
Case-control study—If applicable, explain how matching of
cases and controls was addressed
Cross-sectional study—If applicable, describe analytical
methods taking account of sampling strategy
(e) Describe any sensitivity analyses
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg
numbers potentially eligible, examined for eligibility, confirmed
eligible, included in the study, completing follow-up, and analyzed
(b) Give reasons for non-participation at each stage
(c) Consider use of a flow diagram
Descriptive data 14* (a) Give characteristics of study participants (eg demographic,
clinical, social) and information on exposures and potential
confounders
(b) Indicate number of participants with missing data for each
variable of interest
(c) Cohort study—Summarize follow-up time (eg, average and total
amount)
Outcome data 15* Cohort study—Report numbers of outcome events or summary
measures over time
Case-control study—Report numbers in each exposure category, or
summary measures of exposure
Cross-sectional study—Report numbers of outcome events or
summary measures
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted
estimates and their precision (eg, 95% confidence interval). Make
clear which confounders were adjusted for and why they were
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included
(b) Report category boundaries when continuous variables were
categorized
(c) If relevant, consider translating estimates of relative risk into
absolute risk for a meaningful time period
Other analyses 17 Report other analyses done—eg analyses of subgroups and
interactions, and sensitivity analyses
Discussion
Key results 18 Summarize key results with reference to study objectives
Limitations 19 Discuss limitations of the study, taking into account sources of
potential bias or imprecision. Discuss both direction and magnitude
of any potential bias
Interpretation 20 Give a cautious overall interpretation of results considering
objectives, limitations, multiplicity of analyses, results from similar
studies, and other relevant evidence
Generalizability 21 Discuss the generalizability (external validity) of the study results
Other information
Funding 22 Give the source of funding and the role of the funders for the present
study and, if applicable, for the original study on which the present
article is based
*Give information separately for cases and controls in case-control studies and, if applicable,
for exposed and unexposed groups in cohort and cross-sectional studies.
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Prevalence and incidence of pulmonary hypertension among HIV-infected people in Africa: a systematic review and
meta-analysis
Journal: BMJ Open
Manuscript ID bmjopen-2016-011921.R1
Article Type: Research
Date Submitted by the Author: 11-Jul-2016
Complete List of Authors: Bigna, Jean Joel; Centre Pasteur of Cameroon, Epidemiology and Public Health; University of Bordeaux, Bordeaux School of Public Health Nansseu, Jobert Richie; Mother and Child Centre, Chantal Biya Foundation, Sickle cell unit; Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Department of Public Health Um, Lewis; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Noumegni, Steve Raoul; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Simé, Sandra Paule; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Aminde, Leopold; Clinical Research Education, Networking & Consultancy (CRENC), Douala, Koulla-Shiro, Sinata; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences; Yaoundé Central Hospital, Infectious Diseases Unit Noubiap, Jean Jacques; Groote Schuur Hospital and University of Cape Town, Department of Medicine
<b>Primary Subject Heading</b>:
Respiratory medicine
Secondary Subject Heading: Epidemiology, HIV/AIDS, Public health
Keywords: Pulmonary hypertension, Pulmonary arterial hypertension, HIV & AIDS < INFECTIOUS DISEASES, Africa, Review
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Prevalence and incidence of pulmonary hypertension among HIV-infected
people in Africa: a systematic review and meta-analysis
Jean Joel R. Bigna1, 2*
Jobert Richie N. Nansseu3, 4
Lewis N. Um5 ([email protected])
Steve Raoul N. Noumegni5 ([email protected])
Paule Sandra D. Simé5 ([email protected])
Leopold N. Amindé6, 7
Sinata Koulla-Shiro5, 8
Jean Jacques N. Noubiap9, 10
1Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé,
Cameroon 2Bordeaux School of Public Health, University of Bordeaux, Bordeaux, France
3Department of Public Health, Faculty of Medicine and Biomedical Sciences, University of
Yaoundé 1, Yaoundé, Cameroon 4Sickle Cell Disease Unit, Mother and Child Centre of the Chantal Biya Foundation,
Yaoundé, Cameroon 5Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé,
Cameroon 6School of Public Health, Faculty of Medicine & Biomedical Sciences, University of
Queensland, Brisbane, Australia 7 Clinical Research Education, Networking and Consultancy (CRENC), Douala, Cameroon
8Infectious Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon
9Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape
Town, South Africa
10Medical Diagnosis Center, Yaoundé, Cameroon
* Correspondence to: Dr Jean Joel R. Bigna, Department of Epidemiology and Public Health,
Centre Pasteur of Cameroon, PO Box 1274, Yaoundé, Cameroon; Email:
Keywords
Pulmonary arterial hypertension, pulmonary hypertension, HIV, AIDS, Africa
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Abstract
Objective: Patients infected with HIV have a direly increased risk of developing pulmonary
hypertension (PH), and of dying from the condition. While Africa carries the greatest burden
of HIV infection worldwide, there is unclear data summarizing the epidemiology of PH
among HIV-infected people in this region. Our objective was to determine the prevalence and
incidence of PH in African people living across Africa.
Design: A systematic review and meta-analysis.
Participants: African HIV-infected people residing inside Africa.
Outcome: Prevalence and incidence of PH diagnosed through echocardiography or right
heart catheterization.
Data sources: Articles published in PubMed/Medline, EMBASE, African Journals Online,
and African Index Medicus between 1 January 1980 and 30 June 2016, without any language
restriction.
Results
Overall, 93 studies were screened, three were included in this review: two from Southern
Africa (Tanzania and South Africa) and one from Central Africa (Cameroon). These studies
included HIV adults patients selected based on presentation with cardiovascular complaints.
No study reported PH incidence or PH incidence/prevalence among children and adolescents.
The quality assessment yielded moderate risk of bias. Ages of participants ranged between
18-78 years, and the proportion of females varied between 52.3-68.8%. The prevalence of PH
in the pooled sample of 664 patients was 14% (95% CI: 6–23%).
Limitations: Only three studies found eligible from only two regions in Africa.
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Conclusion: The prevalence of PH among HIV-infected people in Africa is very high.
Further studies are urgently warranted, to determine the incidence of HIV-induced PH and
include all sub-regions of Africa.
Funding: None.
Registration: PROSPERO CRD42016033863.
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Strengths and limitations
• Only 3 studies were eligible from only two regions in Africa.
• It was impossible to disaggregate data between patients on antiretroviral treatment and
those naïve for antiretroviral treatment.
• This is the first meta-analysis summarizing prevalence of pulmonary hypertension among
HIV-infected people in Africa.
• This systematic review and meta-analysis used strong and robust statistical methods, and
figured out an elevated relative prevalence of pulmonary hypertension in HIV-infected
individuals residing in Africa.
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Introduction
HIV continues to be a major global public health issue, having hampered more than 34
million lives so far. There were approximately 36.9 million people living with HIV at the end
of 2014, with 2.0 million people becoming newly infected worldwide; what’s worse, 1.2
million people died from HIV-related consequences in 2014. Sub-Saharan Africa (SSA) is
the most affected region with 25.8 million people living with HIV in 2014. Besides, SSA
accounts for almost 70% of the global HIV new infections.1 2
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) ≥ 25
mmHg on right heart catheterization at rest.3 4
The classification of PH includes: pulmonary
arterial hypertension (PAH), PH due to left heart diseases, PH due to respiratory diseases
and/or hypoxemia, PH due to chronic embolic disease, and PH having unclear multifactorial
mechanisms.3 To date, evidence has accumulated a causal relationship between HIV infection
and PAH.5 The pathogenesis of PAH is complex. From what is known, this may probably
result from the interaction between multiple modulating genes and environmental factors.
The physiopathology includes: (i) cytokines secretion increase which induces a dysregulation
of endothelial and vascular smooth muscle cell growth and an imbalance between
endogenous vasodilators and constrictors; (ii) HIV viral proteins proliferation which induces
vascular oxidative stress, smooth myocyte proliferation and migration, and endothelial injury;
and (iii) genetic predisposition due to some major histocompatibility complex alleles,
particularly HDL-DR6 and HLA-DR5.5
HIV-infected patients have a greater incidence of PH and almost a 2500-fold increased risk of
developing the condition, in comparison with the general population (incidence of idiopathic
PAH: 1-2 per million persons).6 7
Furthermore, the development of PAH in HIV infected
individuals reduces the probability of survival by half in these patients as compared with their
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counterparts without HIV-induced PAH. About two thirds of deaths in patients with HIV-
induced PAH are due to the consequences of PAH such as: right heart failure, cardiogenic
shock, and sudden death.8
While Africa carries the highest burden of HIV infection globally,1 2
there is unclear data
summarizing the epidemiology of PH in HIV-infected populations. Willing to fill this critical
gap, we conducted a systematic-review and meta-analysis, the objective of which was to
determine the prevalence and incidence of PH among African HIV-infected people residing
inside Africa.
Methods
The preferred reporting items for systematic reviews and meta-analyses guidelines served as
the template for reporting the present review.9 The preferred reporting items for systematic
reviews and meta-analyses checklist can be found in S1 Appendix. This review was
registered in the PROSPERO International Prospective Register of systematic reviews,
registration number CRD42016033863.
Eligibility criteria for considering studies to include in the review
Inclusion criteria
- Cross-sectional, case-control or cohort studies of HIV-infected people residing in African
countries which have reported the prevalence or incidence of PH, or enough data to
compute these estimates.
- Studies in which diagnosis of PH was based on right heart catheterization finding the
mPAP ≥ 25 mmHg or abnormal echocardiography exam for pulmonary arterial systolic
pressure > 35 mmHg.3 4
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- We considered all published and unpublished studies reported from 1st January 1980 to 30
June 2016. No language restriction was applied.
Exclusion criteria
- Studies conducted among populations of African origin residing outside Africa.
- Studies not performed in human subjects.
- Studies in subgroups of participants selected on the basis of presence of PH.
- Case series, reviews, letters, commentaries and editorials.
- Studies lacking primary data and/or explicit method description.
For duplicate reports, the most comprehensive and up-to-date version was considered for this
review
Search strategy for identifying relevant studies
The search strategy was implemented in two stages:
Bibliographic database search
We performed a comprehensive and exhaustive search of PubMed/Medline, Excerpta Medica
Database (EMBASE), African Journals Online, and African Index Medicus to identify all
relevant articles published on PH among HIV-infected people in Africa between 1st January
1980 and 30 June 2016, without any language restriction. We conceived and applied a search
strategy based on the combination of relevant terms and names of each of the 54 African
countries and African sub-regions. We used the following terms for PH: “pulmonary
hypertension” and “pulmonary arterial hypertension”. For HIV, we used the terms “HIV” and
“AIDS”. The last electronic search was run on July 1st, 2016. The main search strategy
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conducted in PubMed is shown in S2 Appendix. This search strategy was adapted to fit with
other databases.
Searching other sources
We conducted manual searches which consisted in scanning the reference lists of eligible
papers and other relevant review articles, specialist journals and conference proceedings
(Advances in Pulmonary Hypertension; Pulmonary Hypertension Association’s International
PH Conference, Pulmonary Hypertension Association-Ireland’s Annual Conference, Annual
Scientific Meeting of Pulmonary Hypertension Society of Australia and New Zealand, and
Annual Joint Pulmonary Hypertension).
Selection of studies for inclusion in the review
Two investigators (JJRB and LNU) independently identified articles and sequentially
screened their titles and abstracts for eligibility. Full texts of articles deemed potentially
eligible were acquired. These investigators further independently assessed the full text of
each study for eligibility, and consensually retained studies to be included. Disagreements
when existing were solved by a third author (JRNN). We used a screening guide to ensure
that the selection criteria were reliably applied by all review authors.
Data extraction and management
Two investigators (JJRB and LNU) independently extracted data pertaining to general
information (authors, year, country, region), study characteristics (study design, setting,
sample size, mean or median age and proportion of female participants, diagnosis criteria for
PH, antiretroviral therapy), prevalence and/or incidence of PH. Where only primary data
(sample size and number of outcomes) were provided, these data were used to calculate the
prevalence or incidence estimates. Data were extracted using a preconceived and
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standardized data abstraction form. Disagreements between authors were reconciled through
discussion and consensus, or arbitration by a third author (JRNN) whenever necessary.
Appraisal of the quality of included studies
We evaluated included studies for methodological quality and risk of bias using an adapted
version of the Risk of Bias Tool for Prevalence Studies developed by Hoy et al (Appendix
S3).10
Furthermore, the reporting quality of each study was assessed using the STROBE
checklist (Appendix S4).11
Data synthesis and analysis
Data were analyzed using STATA version 13.0 for Windows. Forest plots were drawn to
visualize the combined prevalence and extent of heterogeneity between studies. Due to
clinical differences across patients included in the studies (difference in the clinical
presentation of patients with cardiac complaints, inconsistency regarding antiretroviral
therapy), a random-effects meta-analysis was used to pool prevalence data,12
after stabilizing
the variance of individual studies with the use of Freeman-Tukey double arc-sine
transformation.13
Heterogeneity was assessed using the χ2 test on Cochrane’s Q statistic,
14
and quantified by calculating the I2 (with values of 25 %, 50 % and 75 % being representative
of low, medium and high heterogeneity respectively).15
In order to assess possible publication
bias, Egger weighted regression methods were used.16
A p-value < 0.05 was considered
indicative of statistically significant publication bias.
Results
Characteristics of included studies
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Initially, a total of 121 articles were identified (Fig 1). After elimination of duplicates,
screening titles and abstracts, 106 papers were found completely irrelevant; they were
consequently excluded. Then, full-texts of the remaining 15 studies were scrutinized for
eligibility, among which 12 studies were excluded, among which two studies where the cut-
off to diagnose PH was 25 mmHg rather than 35 mmHg on echocardiography.17 18
Concerning these two studies, the prevalence was 6.9% among adolescents in Zimbabwe17
,
and 4.0% among adult in Nigeria.18
Overall, three studies were found eligible, hence were
included in the meta-analysis (Fig 1).
Figure 1. Process of identification and selection of studies for inclusion in the review
(PRISMA flow diagram).
All the three studies reported the prevalence of PH without any analysis with regard to the
patients’ ART regimens; none reported the incidence of the condition. The studies were
reported from Cameroon, Tanzania and South Africa; there was no study from the Western,
Eastern or Northern parts of Africa. They were conducted between 2006 and 2014, were
published between 2012 and 2015, and included adult patients who were selected based on
presentation with cardiovascular complaints. Characteristics of these studies are summarized
in Table 1. The female proportion varied from 52.3 to 68.8% (Table 1). For one of the three
studies,19
we calculated the overall prevalence since it has separately been reported the
prevalence for men and that for women. For the two other studies, we reported the prevalence
of PH as it appeared in these studies.20 21
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Table 1. Characteristics of studies included in the meta-analysis 1
First
author,
year of
publication
Study
period
Study
design
Countries Geograph
ical
region
Patient
presentation
Diagnosis
method
Diagnosis
criterion of
PAH
Duration
on ARTa
Popula
tion
size
Number
of
patients
with
pulmonar
y
hypertens
ion (%)
Mean
age
(range)
, years
Nu
mbe
r of
fem
ale
(%)
Chillo,
2012 21
2009-
2010
Cross
sectional
Tanzania Southern
Africa
Selected based on
cardiovascular
complaints
Echocardio
graphy
PASP ≥ 35
mmHg
Not
reported
102 13 (12.7) 42.4
(18-72)
70
(68.
6%)
Menanga,
2015 20
2014 Cross
sectional
Cameroon Central
Africa
Selected based on
cardiovascular
complaints
Echocardio
graphy
PASP ≥ 35
mmHg
Mean
37,3
months
44 13 (29.5) 48.5
(42-72)
23
(52.
3%)
Sliwa, 2012 19
2006-
2008
Cross
sectional
South
Africa
Southern
Africa
Selected based on
cardiovascular
complaints
Echocardio
graphy
PASP ≥ 35
mmHg
Not
reported
518 42 (518) 40 (18-
72)
321
(62
%) aAll studies included patients on antiretroviral therapy and those who were not; the duration is obviously for patients on ART 2
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Considering STROBE guidelines, the quality of reporting was good/fair for all included 1
studies. These studies had a moderate risk of bias (Table 2). 2
Table 2. Quality assessment of included studies 3
STROBE quality of reporting* Risk of bias by Hol et al. £
Score range, 0
to 22
Interpretation Score range,
0 to 10
Interpretation
Chillo, 2012 21 17 Good/fair
quality
7 Moderate risk
Menanga, 2015 20
19 Good/fair
quality
7 Moderate risk
Sliwa, 2012 19
19 Good/fair
quality
6 Moderate risk
*A quality assessment score out of 22 was determined for each study by assigning a point per 4
STROBE item addressed. Good/fair quality papers were categorized as having a score of ≥ 5
14/22 and poor quality papers were classified as having a score of <14/22.11
6
£ Low risk of bias: 8 or more. Moderate risk of bias: 6 to 7. High risk of bias: 5 or fewer.
10 7
8
Pooled prevalence of pulmonary hypertension among HIV-infected people in Africa 9
There was a wide variation in PH prevalence (Fig 2). The heterogeneity was high (I2
= 81.4%, 10
p < 0.001). The prevalence of PH in the pooled sample of 664 individuals was 14% (95% 11
confidence interval [CI], 6–23%). No evidence of publication bias was observed (Fig 3); 12
results of Egger’s weighted regression test did not show any bias of publication (t = 4.09, p = 13
0.153). 14
Figure 2. Forest plots of pulmonary hypertension prevalence among HIV-infected 15
people in Africa. 16
ES: estimated size; CI: confidence intervals; se(ES): standard error of estimated size. 17
18
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Figure 3. Funnel plots of standard errors of pulmonary hypertension prevalence among 1
HIV-infected people in Africa. 2
ES: estimated size; CI: confidence intervals 3
4
5
Discussion 6
These moderate risk of bias studies conducted between 2006 and 2014 from two WHO 7
regions of Africa showed a pooled 14% (95%CI 6-23%) prevalence of PH among African 8
HIV-infected adults. The prevalence of PH among HIV-infected people in Africa found in 9
this meta-analysis is close to what was reported in a recent narrative review (5-13%) 10
targeting the same population.5 This prevalence in sub-Saharan Africa is notably higher when 11
compared to that reported for developed countries, which is around 0.5%.7 22-24
Certain 12
reasons can explain this large discrepancy observed. Indeed, access and retention in care are 13
lower in low- and middle-income countries (including most of African countries) leading to 14
late diagnosis and management of the HIV infection. Consequently, patients will probably 15
arrive at a more advanced stage of disease progression. Besides, ART initiation in developed 16
countries does not take into consideration the CD4 count and HIV clinical stage by contrast 17
to the developing world where these parameters were taken into account, leading to initiation 18
of ART perhaps when HIV-induced complications such as PH have already started to 19
develop.25-28
20
However, it is hoped that the new WHO recommendations for initiating ART regardless of 21
CD4 count (“test and treat” policy) will probably lead to a change in the epidemiology of PH 22
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in HIV infected people in Africa.29
Indeed, it may lead to a decrease in the prevalence of PH 1
in this group of patients.30 2
For now, there is no cure for pulmonary arterial hypertension.31
Nonetheless, the use of 3
highly active antiretroviral therapy (HAART), whose aim is to prevent the multiplication of 4
the virus and thus make undetectable the viral load, could considerably reduce the risk of 5
development or progression of PH in HIV infected patients. It has been demonstrated indeed 6
that detection of plasma HIV-RNA was associated with an increased risk of developing PH.22
7
This suggests also that early initiation of HAART may prevent or delay PH apparition in HIV 8
infected individuals, though data in this regard are controversial.32
Anyway, highly active 9
ART should not be used as a sole therapy for HIV-induced PAH; early initiation of PAH-10
specific management is of paramount importance. In fact, HAART only ameliorates the 11
outcome of patients with HIV-induced PAH.5 12
Two interesting studies were excluded from meta-analysis because authors had diagnosed PH 13
with a cut-off of 25 mmHg for pulmonary arterial systolic pressure using echocardiography.17
14
18 We suggest to researchers and clinicians to adhere to updated guidelines for diagnosis of 15
PH. 16
17
Limitations 18
Our study presents some flaws. First, our study was based on a limited number of published 19
studies. Nonetheless, we explored four databases. Second, concerning quality of evidence, 20
risk of bias of included studies was moderate suggesting that further research is likely to have 21
an important impact on our confidence in the estimate, and may change this estimate. 22
Although there is no publication bias, this study may lack power due to limited number of 23
included studies. Third, considering that almost all studies included were hospital-based, it is 24
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likely that the pooled prevalence of PH we have obtained is symptom-driven. Moreover, none 1
of the studies included in this review assessed the incidence of HIV-induced PAH as well as 2
the relationship between the condition and antiretroviral therapy (ART) (difference between 3
ART+ and ART- patients, the specific regimens increasing the risk, and duration of ART at 4
which PH is likely to occur). Meta-analysis of small number of studies can be questionable; 5
notwithstanding, it gives an overview of the burden of PH among HIV infected people in 6
Africa. Therefore, high-quality observational studies are warranted to fill these crucial gaps. 7
The ongoing PAPUCO cohort study is welcome for bringing some scientific information for 8
PH in African countries.33 9
10
Conclusions 11
This study has shown that more than one African HIV infected adult on ten has PH, which is 12
high, and may direly contribute in the elevated HIV-related mortality rate witnessed all-round 13
Africa. Therefore, health care providers must be aware of this reality, and potentially 14
undertake regular screening for PH in their HIV infected patients, and management tailored 15
accordingly for those diagnosed with the condition. Besides, it should be discussed early 16
during initiation of HAART in African countries to curtail the burden of HIV-induced PAH 17
as well as other HIV-related complications. The new 2015 World Health Organization 18
guidelines on initiation of ART regardless CD4 count, age, and HIV disease progression are 19
highly in the region. Further studies including registries are urgently warranted, which among 20
others should determine the incidence of HIV-induced PAH, and the relation between PAH 21
and ART in HIV infected individuals residing inside Africa. 22
23
24
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Authors’ contributions 1
Study conception and design: JJRB. Search strategy: JJRB and LNA. Study selection: JJRB 2
and LNU. Data extraction: JJRB and LNU. Statistical analysis: JJRB. Data interpretation: 3
JJRB and JRNN. Drafting: JJRB. Manuscript reviewing and revision: JJRB, JRNN, LNA, 4
LNU, SRNN, PSDS, JJNN, SK-S. All authors approved the final version to publish. 5
6
Funding 7
This research received no specific grant from any funding agency in the public, commercial 8
or not-for-profit sectors. 9
10
Competing interests 11
We have read and understood BMJ policy on declaration of interests and declare that we have 12
no competing interests. 13
14
Data sharing statement 15
No additional data are available. 16
17
References 18
1. World Health Organization. HIV/AIDS: Fact sheet N°360. Secondary HIV/AIDS: Fact 19
sheet N°360 2015 July 2015. http://www.who.int/mediacentre/factsheets/fs360/en/. 20
2. UNAIDS. 2014 Global Statistics. Secondary 2014 Global Statistics 2014. 21
http://www.unaids.org/sites/default/files/media_asset/20150714_FS_MDG6_Report_22
en.pdf. 23
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5. Bigna JJ, Sime PS, Koulla-Shiro S. HIV related pulmonary arterial hypertension: 7
epidemiology in Africa, physiopathology, and role of antiretroviral treatment. AIDS 8
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hypertension: from bedside to the future. European journal of clinical investigation 11
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7. Crothers K, Huang L, Goulet JL, et al. HIV infection and risk for incident pulmonary 13
diseases in the combination antiretroviral therapy era. American journal of respiratory 14
and critical care medicine 2011;183(3):388-95. 15
8. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension. 16
A case control study. Swiss HIV Cohort Study. American journal of respiratory and 17
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9. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 19
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11. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of 24
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Bmj 2003;327(7414):557-60. 28
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graphical test. BMJ 1997;315(7109):629-34. 36
17. Ferrand RA, Desai SR, Hopkins C, et al. Chronic lung disease in adolescents with 37
delayed diagnosis of vertically acquired HIV infection. Clinical infectious diseases : 38
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an official publication of the Infectious Diseases Society of America 2012;55(1):145-1
52. 2
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hypertension to HIV-related cardiac dysfunction. Indian heart journal 2013;65(5):644-4
9. 5
19. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency 6
virus/acquired immunodeficiency syndrome epidemic to de novo presentations of 7
heart disease in the Heart of Soweto Study cohort. European heart journal 8
2012;33(7):866-74. 9
20. Menanga AP, Ngomseu CK, Jingi AM, et al. Patterns of cardiovascular disease in a group 10
of HIV-infected adults in Yaounde, Cameroon. Cardiovasc Diagn Ther 11
2015;5(6):420-7. 12
21. Chillo P, Bakari M, Lwakatare J. Echocardiographic diagnoses in HIV-infected patients 13
presenting with cardiac symptoms at Muhimbili National Hospital in Dar es Salaam, 14
Tanzania. Cardiovascular journal of Africa 2012;23(2):90-7. 15
22. Quezada M, Martin-Carbonero L, Soriano V, et al. Prevalence and risk factors associated 16
with pulmonary hypertension in HIV-infected patients on regular follow-up. AIDS 17
2012;26(11):1387-92. 18
23. Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. 19
Chest 1991;100(5):1268-71. 20
24. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary 21
arterial hypertension in the current antiretroviral therapy era. American journal of 22
respiratory and critical care medicine 2008;177(1):108-13. 23
25. Kassaye SG, Katzenstein D. HIV/AIDS care and treatment in sub-Saharan Africa. AIDS 24
reviews 2003;5(4):195-204. 25
26. Giuliano M, Vella S. Inequalities in health: access to treatment for HIV/AIDS. Annali 26
dell'Istituto superiore di sanita 2007;43(4):313-6. 27
27. Shors AR. The global epidemiology of HIV/AIDS. Dermatologic clinics 2006;24(4):413-28
20, v. 29
28. Cleary S. Equity and efficiency in scaling up access to HIV-related interventions in 30
resource-limited settings. Current opinion in HIV and AIDS 2010;5(3):210-4. 31
29. World Health Organization. Guideline on when to start antiretroviral therapy and on pre-32
exposure prophylaxis for HIV. Secondary Guideline on when to start antiretroviral 33
therapy and on pre-exposure prophylaxis for HIV 2015. 34
http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf. 35
30. Jamieson D, Kellerman SE. The 90 90 90 strategy to end the HIV Pandemic by 2030: Can 36
the supply chain handle it? Journal of the International AIDS Society 37
2016;19(1):20917. 38
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31. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 1
2004;351(16):1655-65. 2
32. Torre D, Pugliese A. Impact of antiretroviral therapy among HIV-1-infected patients with 3
pulmonary hypertension. Clinical infectious diseases : an official publication of the 4
Infectious Diseases Society of America 2004;39(10):1549-50; author reply 50. 5
33. Thienemann F, Dzudie A, Mocumbi AO, et al. Rationale and design of the Pan African 6
Pulmonary hypertension Cohort (PAPUCO) study: implementing a contemporary 7
registry on pulmonary hypertension in Africa. BMJ open 2014;4(10):e005950. 8
9
10
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Figure 1. Process of identification and selection of studies for inclusion in the review (PRISMA flow diagram).
338x190mm (300 x 300 DPI)
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Figure 2. Forest plots of pulmonary hypertension prevalence among HIV-infected people in Africa.
ES: estimated size; CI: confidence intervals; se (ES): standard error of estimated size.
190x132mm (600 x 600 DPI)
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Figure 3. Funnel plots of standard errors of pulmonary hypertension prevalence among HIV-infected people in Africa.
ES: estimated size; CI: confidence intervals
139x101mm (300 x 300 DPI)
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S1 Appendix. PRISMA checklist.
Section/topic # Checklist item Reported on page #
TITLE 1
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT 2-3
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2-3
INTRODUCTION 5-6
Rationale 3 Describe the rationale for the review in the context of what is already known. 5-6
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
6
METHODS 6-9
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
6
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 6-7
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
7-8
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
8
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 8
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
8
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
8
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Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
9
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 9
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency
(e.g., I2) for each meta-analysis. 9
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
9
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
9
RESULTS 9-12
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
10
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
10-11
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 12
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
11-12
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 12
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 12
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 12
DISCUSSION 13-15
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
13
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
14-15
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 15
FUNDING 16
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Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
16
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S2 Appendix. Pubmed/Medline search strategy for studies published between January
1st, 1980 and June 30, 2016
Search Search terms
#1 "Pulmonary hypertension" OR "Pulmonary arterial hypertension"
#2 “HIV” OR “AIDS”
#3 (Africa OR Algeria OR Angola OR Benin OR Botswana OR "Burkina Faso"
OR Burundi OR Cameroon OR "Canary Islands" OR "Cape Verde" OR
"Central African Republic" OR Chad OR Comoros OR Congo OR "Democratic
Republic of Congo" OR Djibouti OR Egypt OR "Equatorial Guinea" OR Eritrea
OR Ethiopia OR Gabon OR Gambia OR Ghana OR Guinea OR "Guinea
Bissau" OR "Ivory Coast" OR "Cote d'Ivoire" OR Jamahiriya OR Kenya OR
Lesotho OR Liberia OR Libya OR Madagascar OR Malawi OR Mali OR
Mauritania OR Mauritius OR Mayotte OR Morocco OR Mozambique OR
Namibia OR Niger OR Nigeria OR Principe OR Reunion OR Rwanda OR "Sao
Tome" OR Senegal OR Seychelles OR "Sierra Leone" OR Somalia OR "South
Africa" OR "St Helena" OR Sudan OR Swaziland OR Tanzania OR Togo OR
Tunisia OR Uganda OR "Western Sahara" OR Zaire OR Zambia OR Zimbabwe
OR "Central Africa" OR "Central African" OR "West Africa" OR "West
African" OR "Western Africa" OR "Western African" OR "East Africa" OR
"East African" OR "Eastern Africa" OR "Eastern African" OR "North Africa"
OR "North African" OR "Northern Africa" OR "Northern African" OR "South
African" OR "Southern Africa" OR "Southern African" OR "sub Saharan
Africa" OR "sub Saharan African" OR "subSaharan Africa" OR "subSaharan
African") NOT ("guinea pig" OR "guinea pigs" OR "aspergillus niger")
#4 #1 AND #2 AND #3
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S3 Appendix. Risk of bias assessment tool, adapted from the Risk of Bias Tool for
Prevalence Studies developed by Hoy et al.
Risk of Bias Item Answer:
Yes (Low Risk) or No
(High risk)
External Validity
1. Was the study target population a close representation of
the general HIV population in relation to relevant variables?
2. Was the sampling frame a true or close representation of the
target population?
3. Was some form of random selection used to select the
sample, OR, was a census undertaken?
4. Was the likelihood of non-participation bias minimal?
Internal Validity
5. Were data collected directly from the subjects (as opposed
to medical records)?
6. Were acceptable case definition of pulmonary arterial
hypertension used?
7. Was a reliable and accepted diagnosis method pulmonary
arterial hypertension utilized?
8. Was the same mode of data collection used for all subjects?
9. Was the length of the shortest prevalence period for the
parameter of interest appropriate?
10. Were the numerator(s) and denominator(s) for the
calculation of the prevalence of pulmonary arterial
hypertension appropriate?
Summary item on the overall risk of study bias
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Appendix S4. STROBE Statement: checklist of items that should be included in reports
of observational studies
Item
No Recommendation
Title and abstract 1 (a) Indicate the study’s design with a commonly used term
in the title or the abstract
(b) Provide in the abstract an informative and balanced
summary of what was done and what was found
Introduction
Background/rationale 2 Explain the scientific background and rationale for the
investigation being reported
Objectives 3 State specific objectives, including any prespecified
hypotheses
Methods
Study design 4 Present key elements of study design early in the paper
Setting 5 Describe the setting, locations, and relevant dates, including
periods of recruitment, exposure, follow-up, and data
collection
Participants 6 (a) Cohort study—Give the eligibility criteria, and the
sources and methods of selection of participants. Describe
methods of follow-up
Case-control study—Give the eligibility criteria, and the
sources and methods of case ascertainment and control
selection. Give the rationale for the choice of cases and
controls
Cross-sectional study—Give the eligibility criteria, and the
sources and methods of selection of participants
(b) Cohort study—For matched studies, give matching
criteria and number of exposed and unexposed
Case-control study—For matched studies, give matching
criteria and the number of controls per case
Variables 7 Clearly define all outcomes, exposures, predictors, potential
confounders, and effect modifiers. Give diagnostic criteria, if
applicable
Data sources/
measurement
8* For each variable of interest, give sources of data and details
of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than
one group
Bias 9 Describe any efforts to address potential sources of bias
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Study size 10 Explain how the study size was arrived at
Quantitative variables 11 Explain how quantitative variables were handled in the
analyses. If applicable, describe which groupings were
chosen and why
Statistical methods 12 (a) Describe all statistical methods, including those used to
control for confounding
(b) Describe any methods used to examine subgroups and
interactions
(c) Explain how missing data were addressed
(d) Cohort study—If applicable, explain how loss to follow-
up was addressed
Case-control study—If applicable, explain how matching of
cases and controls was addressed
Cross-sectional study—If applicable, describe analytical
methods taking account of sampling strategy
(e) Describe any sensitivity analyses
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg
numbers potentially eligible, examined for eligibility, confirmed
eligible, included in the study, completing follow-up, and analyzed
(b) Give reasons for non-participation at each stage
(c) Consider use of a flow diagram
Descriptive data 14* (a) Give characteristics of study participants (eg demographic,
clinical, social) and information on exposures and potential
confounders
(b) Indicate number of participants with missing data for each
variable of interest
(c) Cohort study—Summarize follow-up time (eg, average and total
amount)
Outcome data 15* Cohort study—Report numbers of outcome events or summary
measures over time
Case-control study—Report numbers in each exposure category, or
summary measures of exposure
Cross-sectional study—Report numbers of outcome events or
summary measures
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted
estimates and their precision (eg, 95% confidence interval). Make
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clear which confounders were adjusted for and why they were
included
(b) Report category boundaries when continuous variables were
categorized
(c) If relevant, consider translating estimates of relative risk into
absolute risk for a meaningful time period
Other analyses 17 Report other analyses done—eg analyses of subgroups and
interactions, and sensitivity analyses
Discussion
Key results 18 Summarize key results with reference to study objectives
Limitations 19 Discuss limitations of the study, taking into account sources of
potential bias or imprecision. Discuss both direction and magnitude
of any potential bias
Interpretation 20 Give a cautious overall interpretation of results considering
objectives, limitations, multiplicity of analyses, results from similar
studies, and other relevant evidence
Generalizability 21 Discuss the generalizability (external validity) of the study results
Other information
Funding 22 Give the source of funding and the role of the funders for the present
study and, if applicable, for the original study on which the present
article is based
*Give information separately for cases and controls in case-control studies and, if applicable,
for exposed and unexposed groups in cohort and cross-sectional studies.
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Prevalence and incidence of pulmonary hypertension among HIV-infected people in Africa: a systematic review and
meta-analysis
Journal: BMJ Open
Manuscript ID bmjopen-2016-011921.R2
Article Type: Research
Date Submitted by the Author: 30-Jul-2016
Complete List of Authors: Bigna, Jean Joel; Centre Pasteur of Cameroon, Epidemiology and Public Health; University of Bordeaux, Bordeaux School of Public Health Nansseu, Jobert Richie; Mother and Child Centre, Chantal Biya Foundation, Sickle cell unit; Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Department of Public Health Um, Lewis; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Noumegni, Steve Raoul; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Simé, Sandra Paule; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences Aminde, Leopold; Clinical Research Education, Networking & Consultancy (CRENC), Douala, Koulla-Shiro, Sinata; University of Yaoundé 1, Faculty of Medicine and Biomedical Sciences; Yaoundé Central Hospital, Infectious Diseases Unit Noubiap, Jean Jacques; Groote Schuur Hospital and University of Cape Town, Department of Medicine
<b>Primary Subject Heading</b>:
Respiratory medicine
Secondary Subject Heading: Epidemiology, HIV/AIDS, Public health
Keywords: Pulmonary arterial hypertension, Pulmonary hypertension, HIV, AIDS, Africa
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Prevalence and incidence of pulmonary hypertension among HIV-infected
people in Africa: a systematic review and meta-analysis
Jean Joel R. Bigna1, 2*
Jobert Richie N. Nansseu3, 4
Lewis N. Um5 ([email protected])
Steve Raoul N. Noumegni5 ([email protected])
Paule Sandra D. Simé5 ([email protected])
Leopold N. Amindé6, 7
Sinata Koulla-Shiro5, 8
Jean Jacques N. Noubiap9, 10
1Department of Epidemiology and Public Health, Centre Pasteur of Cameroon, Yaoundé,
Cameroon 2Bordeaux School of Public Health, University of Bordeaux, Bordeaux, France
3Department of Public Health, Faculty of Medicine and Biomedical Sciences, University of
Yaoundé 1, Yaoundé, Cameroon 4Sickle Cell Disease Unit, Mother and Child Centre of the Chantal Biya Foundation,
Yaoundé, Cameroon 5Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé,
Cameroon 6School of Public Health, Faculty of Medicine & Biomedical Sciences, University of
Queensland, Brisbane, Australia 7 Clinical Research Education, Networking and Consultancy (CRENC), Douala, Cameroon
8Infectious Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon
9Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape
Town, South Africa
10Medical Diagnosis Center, Yaoundé, Cameroon
* Correspondence to: Dr Jean Joel R. Bigna, Department of Epidemiology and Public Health,
Centre Pasteur of Cameroon, PO Box 1274, Yaoundé, Cameroon; Email:
Keywords
Pulmonary arterial hypertension, pulmonary hypertension, HIV, AIDS, Africa
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Abstract
Objective: Patients infected with HIV have a direly increased risk of developing pulmonary
hypertension (PH), and of dying from the condition. While Africa carries the greatest burden
of HIV infection worldwide, there is unclear data summarizing the epidemiology of PH
among HIV-infected people in this region. Our objective was to determine the prevalence and
incidence of PH among HIV-infected people living across Africa.
Design: A systematic review and meta-analysis.
Participants: African HIV-infected people residing inside Africa.
Outcome: Prevalence and incidence of PH diagnosed through echocardiography or right
heart catheterization.
Data sources: Articles published in PubMed/Medline, EMBASE, African Journals Online,
and African Index Medicus between 1 January 1980 and 30 June 2016, without any language
restriction.
Results: Overall, 121 studies were screened; three were included in this review: one from
Southern Africa (South Africa), one from East Africa (Tanzania) and one from Central Africa
(Cameroon). These studies included HIV-infected adult patients selected based on
presentation with cardiovascular complaints. No study reported PH incidence or PH
incidence/prevalence among children and adolescents. The quality assessment yielded
moderate risk of bias. Ages of participants ranged between 18-78 years, and the proportion of
females varied between 52.3-68.8%. The prevalence of PH in the pooled sample of 664
patients was 14% (95% CI: 6–23%).
Limitations: Only three studies were found eligible from three regions of the African
continent.
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Conclusion: The prevalence of PH among HIV-infected people in Africa seems very high.
Further studies are urgently warranted to determine the incidence of HIV-induced PH, which
must include all sub-regions of Africa.
Funding: None.
Registration: PROSPERO CRD42016033863.
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Strengths and limitations
• Only 3 studies were eligible from three of the five sub-regions of Africa.
• It was impossible to disaggregate data between patients on antiretroviral treatment and
those naïve of antiretroviral treatment.
• This is the first systematic review and meta-analysis summarizing the prevalence of
pulmonary hypertension among HIV-infected people in Africa.
• Strong and robust statistical methods were used, which permitted to figure out an elevated
relative prevalence of pulmonary hypertension in HIV-infected individuals residing inside
Africa.
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Introduction
HIV continues to be a major global public health issue, having hampered more than 34
million lives so far. There were approximately 36.9 million people living with HIV at the end
of 2014, with 2 million people becoming newly infected worldwide; what’s worse, 1.2
million people died from HIV-related consequences in 2014. Sub-Saharan Africa (SSA) is
the most affected region with 25.8 million people living with HIV in 2014. Besides, SSA
accounts for almost 70% of the global HIV new infections.1 2
Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) ≥ 25
mmHg on right heart catheterization at rest.3 4
The classification of PH includes: pulmonary
arterial hypertension (PAH), PH due to left heart diseases, PH due to respiratory diseases
and/or hypoxemia, PH due to chronic thromboembolic disease, and PH due to unclear
multifactorial mechanisms.3 To date, evidence has accumulated a causal relationship between
HIV infection and PAH.5 The pathogenesis of PAH is complex. It is currently admitted that
this may probably result from the interaction between multiple modulating genes and
environmental factors. The physiopathology includes: (i) increase in cytokine secretion
inducing a dysregulation of endothelial and vascular smooth muscle cell growth and an
imbalance between endogenous vasodilators and constrictors; (ii) proliferation of HIV viral
proteins leading to vascular oxidative stress, smooth myocyte proliferation and migration,
and endothelial injury; and (iii) genetic predisposition due to some major histocompatibility
complex alleles, particularly HDL-DR6 and HLA-DR5.5
HIV-infected patients have a greater incidence of PH and almost a 2500-fold increased risk of
developing the condition in comparison with the general population (incidence of idiopathic
PAH: 1-2 per million persons).6 7
Furthermore, the development of PAH in HIV-infected
individuals reduces their probability of survival by half when compared to their counterparts
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without HIV-induced PAH. About two-thirds of deaths in patients with HIV-induced PAH
are due to the consequences of PAH such as: right heart failure, cardiogenic shock, and
sudden death.8
While Africa carries the greatest burden of HIV infection globally,1 2
there is unclear data
summarizing the epidemiology of PH in HIV-infected populations. To fill this critical gap,
we conducted a systematic-review and meta-analysis, with the objective to determine the
prevalence and incidence of PH among African HIV-infected people residing inside Africa.
Methods
The preferred reporting items for systematic reviews and meta-analyses guidelines served as
the template for reporting the present review.9 The preferred reporting items for systematic
reviews and meta-analyses checklist can be found in S1 Appendix. This review was
registered in the PROSPERO International Prospective Register of systematic reviews,
registration number CRD42016033863.
Eligibility criteria for considering studies to include in the review
Inclusion criteria
- Cross-sectional, case-control or cohort studies of HIV-infected people residing in African
countries which have reported the prevalence or incidence of PH, or enough data to
compute these estimates.
- Studies in which diagnosis of PH was based on right heart catheterization finding a mPAP
≥ 25 mmHg or abnormal echocardiography exam for a pulmonary arterial systolic
pressure > 35 mmHg.3 4
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- We considered all published and unpublished studies reported from 1st January 1980 to 30
June 2016. No language restriction was applied.
Exclusion criteria
- Studies conducted among populations of African origin residing outside Africa.
- Studies not performed in human subjects.
- Studies in subgroups of participants selected on the basis of presence of PH.
- Case series, reviews, letters, commentaries and editorials.
- Studies lacking primary data and/or explicit description of methods.
For duplicate reports, the most comprehensive and up-to-date version was considered for this
review.
Search strategy for identifying relevant studies
The search strategy was implemented in two stages:
Bibliographic database search
We performed a comprehensive and exhaustive search of PubMed/Medline, Excerpta Medica
Database (EMBASE), African Journals Online, and African Index Medicus to identify all
relevant articles published on PH among HIV-infected people in Africa between 1st January
1980 and 30 June 2016, without any language restriction. We conceived and applied a search
strategy based on the combination of relevant terms and names of each of the 54 African
countries and African sub-regions. We used the following terms for PH: “pulmonary
hypertension” and “pulmonary arterial hypertension”. For HIV, we used the terms “HIV” and
“AIDS”. The last electronic search was run on July 1st, 2016. The main search strategy
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conducted in PubMed is shown in S2 Appendix. This search strategy was adapted to fit with
other databases.
Searching other sources
We conducted manual searches which consisted in scanning the reference lists of eligible
papers and other relevant review articles, specialist journals and conference proceedings
(Advances in Pulmonary Hypertension; Pulmonary Hypertension Association’s International
PH Conference, Pulmonary Hypertension Association-Ireland’s Annual Conference, Annual
Scientific Meeting of the Pulmonary Hypertension Society of Australia and New Zealand,
and Annual Joint Pulmonary Hypertension).
Selection of studies for inclusion in the review
Two investigators (JJRB and LNU) independently identified articles and sequentially
screened their titles and abstracts for eligibility. Full texts of articles deemed potentially
eligible were acquired. These investigators further independently assessed the full text of
each study for eligibility, and consensually retained studies to be included. Disagreements
when existing were solved by a third author (JRNN). We used a screening guide to ensure
that selection criteria were reliably applied by all review authors. Agreement was measured
using the Kappa statistic.10
Data extraction and management
Two investigators (JJRB and LNU) independently extracted data pertaining to general
information (authors, year, country, region), study characteristics (study design, setting,
sample size, mean or median age and proportion of female participants, diagnosis criteria for
PH, antiretroviral therapy), prevalence and/or incidence of PH. Where only primary data
(sample size and number of outcomes) were provided, these data were used to calculate the
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prevalence or incidence estimates. Data were extracted using a preconceived and
standardized data abstraction form. Disagreements between authors were reconciled through
discussion and consensus, or arbitration by a third author (JRNN) whenever necessary.
Agreement was measured using the Kappa statistic.10
Appraisal of the quality of included studies
Two investigators (JJRB and LNU) evaluated included studies for methodological quality
and risk of bias using an adapted version of the Risk of Bias Tool for Prevalence Studies
developed by Hoy et al. (Appendix S3).11
Furthermore, the reporting quality of each study
was assessed using the STROBE checklist (Appendix S4).12
Agreement was measured using
the Kappa statistic.10
Data synthesis and analysis
Data were analyzed using STATA version 13.0 for Windows. Forest plots were drawn to
visualize the combined prevalence and extent of heterogeneity between studies. Due to the
clinical differences across patients included in the studies (difference in the clinical
presentation of patients with cardiac complaints, inconsistency regarding antiretroviral
therapy), a random-effects meta-analysis was used to pool prevalence data,13
after stabilizing
the variance of individual studies with the use of Freeman-Tukey double arc-sine
transformation.14
Heterogeneity was assessed using the χ2 test on Cochrane’s Q statistic,
15
and quantified by calculating the I2 (with values of 25 %, 50 % and 75 % being representative
of low, medium and high heterogeneity respectively).16
In order to assess possible publication
bias, Egger weighted regression methods were used.17
A p-value < 0.05 was considered
indicative of statistically significant publication bias.
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Results
Characteristics of included studies
Initially, a total of 121 articles were identified (Fig 1). After elimination of duplicates,
screening titles and abstracts, 106 papers were found completely irrelevant and excluded.
Agreement between investigators on abstract selection was high (Kappa = 0.90, p < 0.001;
given a maximum attainable Kappa = 1). Full-texts of the remaining 15 studies were
scrutinized for eligibility, among which 12 studies were excluded. There was no
disagreement between investigators for full text selection. In two of these excluded studies,
the cut-off for diagnosis of PH was 25 mmHg, rather than 35 mmHg on echocardiography.18
19 Concerning these two studies, the prevalence of PH was 6.9% among adolescents in
Zimbabwe18
, and 4% among adults in Nigeria.19
Overall, three studies were found eligible;
hence they were included in the meta-analysis (Fig 1).
Figure 1. Process of identification and selection of studies for inclusion in the review
(PRISMA flow diagram).
All the three studies reported the prevalence of PH without any analysis with regard to the
patients’ ART regimens and none reported the incidence of PH. The studies were reported
from Cameroon, Tanzania and South Africa; there was no study from the Western and
Northern parts of Africa. They were conducted between 2006 and 2014, were published
between 2012 and 2015, and included HIV-adult patients who were selected based on
presentation with cardiovascular complaints. Characteristics of these studies are summarized
in Table 1. The female proportion varied from 52.3 to 68.8% (Table 1). For one of these
studies, 20
we calculated the overall prevalence since it separately reported the prevalence for
men and that for women. For the two other studies, we reported the prevalence of PH as it
appeared in these studies.21 22
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Table 1. Characteristics of studies included in the meta-analysis 1
First
author,
year of
publication
Study
period
Study
design
Countries Geograph
ical
region
Patient
presentation
Diagnosis
method
Diagnosis
criterion of
PAH
Duration
on ARTa
Popula
tion
size
Number
of
patients
with
pulmonar
y
hypertens
ion (%)
Mean
age
(range)
, years
Nu
mbe
r of
fem
ale
(%)
Chillo,
2012 22
2009-
2010
Cross
sectional
Tanzania East
Africa
Selected based on
cardiovascular
complaints
Echocardio
graphy
PASP ≥ 35
mmHg
Not
reported
102 13 (12.7) 42.4
(18-72)
70
(68.
6%)
Menanga,
2015 21
2014 Cross
sectional
Cameroon Central
Africa
Selected based on
cardiovascular
complaints
Echocardio
graphy
PASP ≥ 35
mmHg
Mean
37,3
months
44 13 (29.5) 48.5
(42-72)
23
(52.
3%)
Sliwa, 2012 20
2006-
2008
Cross
sectional
South
Africa
Southern
Africa
Selected based on
cardiovascular
complaints
Echocardio
graphy
PASP ≥ 35
mmHg
Not
reported
518 42 (8.1) 40 (18-
72)
321
(62
%) aAll studies included patients on antiretroviral therapy and those who were not; the duration is obviously for patients on ART 2
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Considering STROBE guidelines, the quality of reporting was good/fair for all included 1
studies. These studies had a moderate risk of bias (Table 2). Agreement between investigators 2
on quality assessment of studies was high (Kappa = 0.88, p < 0.001; given a maximum 3
attainable Kappa = 1). 4
Table 2. Quality assessment of included studies 5
STROBE quality of
reporting*
Risk of bias by Hoy et al. £
Score range,
0 to 22
Interpretation Score range,
0 to 10
Interpretation
Chillo, 2012 22 17 Good/fair
quality
7 Moderate risk
Menanga, 2015 21
19 Good/fair
quality
7 Moderate risk
Sliwa, 2012 20
19 Good/fair
quality
6 Moderate risk
*A quality assessment score out of 22 was determined for each study by assigning a point per 6
STROBE item addressed. Good/fair quality papers were categorized as having a score of ≥ 7
14/22 and poor quality papers were classified as having a score of < 14/22.12
8
£ Low risk of bias: 8 or more. Moderate risk of bias: 6 to 7. High risk of bias: 5 or fewer.
11 9
10
Pooled prevalence of pulmonary hypertension among HIV-infected people in Africa 11
There was a wide variation in PH prevalence (Fig 2). The heterogeneity was high (I2
= 81.4%, 12
p < 0.001). The prevalence of PH in the pooled sample of 664 individuals was 14% (95% 13
confidence interval [CI], 6–23%). No evidence of publication bias was observed (Fig 3); 14
results of Egger’s weighted regression test did not show any bias of publication (t = 4.09, p = 15
0.153). 16
Figure 2. Forest plots of pulmonary hypertension prevalence among HIV-infected 17
people in Africa. 18
ES: estimated size; CI: confidence intervals; se (ES): standard error of estimated size. 19
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1
Figure 3. Funnel plots of standard errors of pulmonary hypertension prevalence among 2
HIV-infected people in Africa. 3
ES: estimated size; CI: confidence intervals 4
5
6
Discussion 7
These moderate risk of bias studies conducted between 2006 and 2014 from three WHO 8
regions of Africa showed a pooled 14% (95%CI 6-23%) prevalence of PH among African 9
HIV-infected adults. The prevalence of PH among HIV-infected people in Africa found in 10
this meta-analysis is close to what was reported in a recent narrative review (5-13%) targeting 11
the same population.5 This prevalence in sub-Saharan Africa is notably higher when 12
compared to that from developed countries, around 0.5%.7 23-25
Certain reasons can explain 13
this large discrepancy observed. Access to and retention in care are lower in low- and middle-14
income countries (including most of African countries), leading to late diagnosis and 15
management of the HIV infection. Consequently, patients will probably arrive at a more 16
advanced stage of disease progression. Besides, ART initiation in developed countries does 17
not take into consideration the CD4-cell count and HIV clinical stage in contrast to the 18
developing world where these parameters are still taken into account, leading to initiation of 19
ART perhaps when processes towards HIV-induced complications such as PH have already 20
commenced.26-29
21
However, it is hoped that the new WHO recommendations for initiating ART regardless of 22
CD4 count (“test and treat” policy) will probably lead to a change in the epidemiology of PH 23
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in HIV infected people in Africa.30
Indeed, it may lead to a decrease in the prevalence of PH 1
in this group of patients.31 2
For now, there is no cure for pulmonary arterial hypertension.32
Nonetheless, the use of 3
highly active antiretroviral therapy (HAART), whose aim is to prevent the multiplication of 4
the virus and thus make undetectable the viral load, could considerably reduce the risk of 5
development or progression of PH in HIV-infected patients. It has been demonstrated that the 6
detection of plasma HIV-RNA was associated with an increased risk of developing PH.23
7
This suggests also that early initiation of HAART may prevent or delay PH apparition in HIV 8
infected individuals, though data in this respect are controversial.33
In any case, HAART 9
should not be used as single therapy for HIV-induced PAH; early initiation of PAH-specific 10
management is of paramount importance. In fact, HAART only ameliorates the outcome of 11
patients with HIV-induced PAH.5 12
Two interesting studies were excluded from our meta-analysis because the authors diagnosed 13
PH with a cut-off of 25 mmHg for pulmonary arterial systolic pressure using 14
echocardiography.18 19
We suggest to researchers and clinicians to adhere to the updated 15
guidelines for the proper diagnosis of PH. 16
17
Limitations 18
Our study presents some flaws. First, our study was based on a limited number of published 19
studies. Nonetheless, we explored four databases. Second, concerning quality of evidence, the 20
risk of bias of included studies was moderate suggesting that further research is likely to have 21
an important impact on our confidence in the estimate, and may change this estimate. 22
Although there is no publication bias, this study may lack power due to the limited number of 23
included studies. Third, considering that almost all studies included were hospital-based, it is 24
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likely that the pooled prevalence of PH we obtained is symptom-driven. Moreover, none of 1
the studies included in this review assessed the incidence of HIV-induced PAH as well as the 2
relationship between the condition and antiretroviral therapy (ART) (difference between 3
ART+ and ART- patients, the specific regimens increasing the risk, and duration of ART at 4
which PH is likely to occur). Meta-analysis of small number of studies can be questionable; 5
notwithstanding, it gives an overview of the burden of PH among HIV infected people in 6
Africa. Therefore, high-quality observational studies are warranted to fill these crucial gaps. 7
The ongoing PAPUCO cohort study is welcome for bringing some scientific information 8
regarding PH in African countries.34 9
10
Conclusions 11
The prevalence of PH among people living with HIV in Africa seems very high, which may 12
significantly contribute to the elevated HIV-related mortality rate witnessed all-round the 13
continent. Therefore, health care providers must be aware of this reality, and potentially 14
undertake regular screening of PH among their HIV infected patients, and management 15
tailored accordingly for those diagnosed with the condition. Besides, it should be discussed 16
early during initiation of HAART in African countries to curtail the burden of HIV-induced 17
PAH as well as other HIV-related complications. The new 2015 World Health Organization 18
guidelines on initiation of ART regardless CD4 count, age, and HIV disease progression are 19
likely to change the epidemiology of PH in this vulnerable population in Africa. Further 20
studies including registries are urgently warranted, which should determine the incidence of 21
HIV-induced PAH, and the relation between PAH and ART in HIV infected individuals 22
residing inside Africa. 23
24
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1
Authors’ contributions 2
Study conception and design: JJRB. Search strategy: JJRB and LNA. Study selection: JJRB 3
and LNU. Data extraction: JJRB and LNU. Statistical analysis: JJRB. Data interpretation: 4
JJRB and JRNN. Drafting: JJRB. Manuscript reviewing and revision: JJRB, JRNN, LNA, 5
LNU, SRNN, PSDS, JJNN, SK-S. All authors approved the final version to publish. 6
7
Funding 8
This research received no specific grant from any funding agency in the public, commercial 9
or not-for-profit sectors. 10
11
Competing interests 12
We have read and understood BMJ policy on declaration of interests and declare that we have 13
no competing interests. 14
15
Data sharing statement 16
No additional data are available. 17
18
References 19
1. World Health Organization. HIV/AIDS: Fact sheet N°360. Secondary HIV/AIDS: Fact 20
sheet N°360 2015 July 2015. http://www.who.int/mediacentre/factsheets/fs360/en/. 21
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hypertension. Journal of the American College of Cardiology 2013;62(25 8
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5. Bigna JJ, Sime PS, Koulla-Shiro S. HIV related pulmonary arterial hypertension: 10
epidemiology in Africa, physiopathology, and role of antiretroviral treatment. AIDS 11
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8. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension. 19
A case control study. Swiss HIV Cohort Study. American journal of respiratory and 20
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16. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in 1
medicine 2002;21(11):1539-58. 2
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graphical test. BMJ 1997;315(7109):629-34. 4
18. Ferrand RA, Desai SR, Hopkins C, et al. Chronic lung disease in adolescents with 5
delayed diagnosis of vertically acquired HIV infection. Clinical infectious diseases : 6
an official publication of the Infectious Diseases Society of America 2012;55(1):145-7
52. 8
19. Isiguzo GC, Okeahialam BN, Danbauchi SS, et al. Contributions of pulmonary 9
hypertension to HIV-related cardiac dysfunction. Indian heart journal 2013;65(5):644-10
9. 11
20. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency 12
virus/acquired immunodeficiency syndrome epidemic to de novo presentations of 13
heart disease in the Heart of Soweto Study cohort. European heart journal 14
2012;33(7):866-74. 15
21. Menanga AP, Ngomseu CK, Jingi AM, et al. Patterns of cardiovascular disease in a group 16
of HIV-infected adults in Yaounde, Cameroon. Cardiovasc Diagn Ther 17
2015;5(6):420-7. 18
22. Chillo P, Bakari M, Lwakatare J. Echocardiographic diagnoses in HIV-infected patients 19
presenting with cardiac symptoms at Muhimbili National Hospital in Dar es Salaam, 20
Tanzania. Cardiovascular journal of Africa 2012;23(2):90-7. 21
23. Quezada M, Martin-Carbonero L, Soriano V, et al. Prevalence and risk factors associated 22
with pulmonary hypertension in HIV-infected patients on regular follow-up. AIDS 23
2012;26(11):1387-92. 24
24. Speich R, Jenni R, Opravil M, et al. Primary pulmonary hypertension in HIV infection. 25
Chest 1991;100(5):1268-71. 26
25. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary 27
arterial hypertension in the current antiretroviral therapy era. American journal of 28
respiratory and critical care medicine 2008;177(1):108-13. 29
26. Kassaye SG, Katzenstein D. HIV/AIDS care and treatment in sub-Saharan Africa. AIDS 30
reviews 2003;5(4):195-204. 31
27. Giuliano M, Vella S. Inequalities in health: access to treatment for HIV/AIDS. Annali 32
dell'Istituto superiore di sanita 2007;43(4):313-6. 33
28. Shors AR. The global epidemiology of HIV/AIDS. Dermatologic clinics 2006;24(4):413-34
20, v. 35
29. Cleary S. Equity and efficiency in scaling up access to HIV-related interventions in 36
resource-limited settings. Current opinion in HIV and AIDS 2010;5(3):210-4. 37
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30. World Health Organization. Guideline on when to start antiretroviral therapy and on pre-1
exposure prophylaxis for HIV. Secondary Guideline on when to start antiretroviral 2
therapy and on pre-exposure prophylaxis for HIV 2015. 3
http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf. 4
31. Jamieson D, Kellerman SE. The 90 90 90 strategy to end the HIV Pandemic by 2030: Can 5
the supply chain handle it? Journal of the International AIDS Society 6
2016;19(1):20917. 7
32. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 8
2004;351(16):1655-65. 9
33. Torre D, Pugliese A. Impact of antiretroviral therapy among HIV-1-infected patients with 10
pulmonary hypertension. Clinical infectious diseases : an official publication of the 11
Infectious Diseases Society of America 2004;39(10):1549-50; author reply 50. 12
34. Thienemann F, Dzudie A, Mocumbi AO, et al. Rationale and design of the Pan African 13
Pulmonary hypertension Cohort (PAPUCO) study: implementing a contemporary 14
registry on pulmonary hypertension in Africa. BMJ open 2014;4(10):e005950. 15
16
17
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Figure 1. Process of identification and selection of studies for inclusion in the review (PRISMA flow diagram).
338x190mm (300 x 300 DPI)
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Figure 2. Forest plots of pulmonary hypertension prevalence among HIV-infected people in Africa.
ES: estimated size; CI: confidence intervals; se (ES): standard error of estimated size.
190x132mm (600 x 600 DPI)
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Figure 3. Funnel plots of standard errors of pulmonary hypertension prevalence among HIV-infected people in Africa.
ES: estimated size; CI: confidence intervals
139x101mm (300 x 300 DPI)
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S1 Appendix. PRISMA checklist.
Section/topic # Checklist item Reported on page #
TITLE 1
Title 1 Identify the report as a systematic review, meta-analysis, or both. 1
ABSTRACT 2-3
Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number.
2-3
INTRODUCTION 5-6
Rationale 3 Describe the rationale for the review in the context of what is already known. 5-6
Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
6
METHODS 6-9
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
6
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered,
language, publication status) used as criteria for eligibility, giving rationale. 6-7
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
7-8
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.
8
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable,
included in the meta-analysis). 8
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
8
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.
8
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Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
9
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 9
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency
(e.g., I2) for each meta-analysis. 9
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
9
Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.
9
RESULTS 9-12
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
10
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.
10-11
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 12
Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
11-12
Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 12
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 12
Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 12
DISCUSSION 13-15
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
13
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).
14-15
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 15
FUNDING 16
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Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.
16
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S2 Appendix. Pubmed/Medline search strategy for studies published between January
1st, 1980 and June 30, 2016
Search Search terms
#1 "Pulmonary hypertension" OR "Pulmonary arterial hypertension"
#2 “HIV” OR “AIDS”
#3 (Africa OR Algeria OR Angola OR Benin OR Botswana OR "Burkina Faso"
OR Burundi OR Cameroon OR "Canary Islands" OR "Cape Verde" OR
"Central African Republic" OR Chad OR Comoros OR Congo OR "Democratic
Republic of Congo" OR Djibouti OR Egypt OR "Equatorial Guinea" OR Eritrea
OR Ethiopia OR Gabon OR Gambia OR Ghana OR Guinea OR "Guinea
Bissau" OR "Ivory Coast" OR "Cote d'Ivoire" OR Jamahiriya OR Kenya OR
Lesotho OR Liberia OR Libya OR Madagascar OR Malawi OR Mali OR
Mauritania OR Mauritius OR Mayotte OR Morocco OR Mozambique OR
Namibia OR Niger OR Nigeria OR Principe OR Reunion OR Rwanda OR "Sao
Tome" OR Senegal OR Seychelles OR "Sierra Leone" OR Somalia OR "South
Africa" OR "St Helena" OR Sudan OR Swaziland OR Tanzania OR Togo OR
Tunisia OR Uganda OR "Western Sahara" OR Zaire OR Zambia OR Zimbabwe
OR "Central Africa" OR "Central African" OR "West Africa" OR "West
African" OR "Western Africa" OR "Western African" OR "East Africa" OR
"East African" OR "Eastern Africa" OR "Eastern African" OR "North Africa"
OR "North African" OR "Northern Africa" OR "Northern African" OR "South
African" OR "Southern Africa" OR "Southern African" OR "sub Saharan
Africa" OR "sub Saharan African" OR "subSaharan Africa" OR "subSaharan
African") NOT ("guinea pig" OR "guinea pigs" OR "aspergillus niger")
#4 #1 AND #2 AND #3
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S3 Appendix. Risk of bias assessment tool, adapted from the Risk of Bias Tool for
Prevalence Studies developed by Hoy et al.
Risk of Bias Item Answer:
Yes (Low Risk) or No
(High risk)
External Validity
1. Was the study target population a close representation of
the general HIV population in relation to relevant variables?
2. Was the sampling frame a true or close representation of the
target population?
3. Was some form of random selection used to select the
sample, OR, was a census undertaken?
4. Was the likelihood of non-participation bias minimal?
Internal Validity
5. Were data collected directly from the subjects (as opposed
to medical records)?
6. Were acceptable case definition of pulmonary arterial
hypertension used?
7. Was a reliable and accepted diagnosis method pulmonary
arterial hypertension utilized?
8. Was the same mode of data collection used for all subjects?
9. Was the length of the shortest prevalence period for the
parameter of interest appropriate?
10. Were the numerator(s) and denominator(s) for the
calculation of the prevalence of pulmonary arterial
hypertension appropriate?
Summary item on the overall risk of study bias
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Appendix S4. STROBE Statement: checklist of items that should be included in reports
of observational studies
Item
No Recommendation
Title and abstract 1 (a) Indicate the study’s design with a commonly used term
in the title or the abstract
(b) Provide in the abstract an informative and balanced
summary of what was done and what was found
Introduction
Background/rationale 2 Explain the scientific background and rationale for the
investigation being reported
Objectives 3 State specific objectives, including any prespecified
hypotheses
Methods
Study design 4 Present key elements of study design early in the paper
Setting 5 Describe the setting, locations, and relevant dates, including
periods of recruitment, exposure, follow-up, and data
collection
Participants 6 (a) Cohort study—Give the eligibility criteria, and the
sources and methods of selection of participants. Describe
methods of follow-up
Case-control study—Give the eligibility criteria, and the
sources and methods of case ascertainment and control
selection. Give the rationale for the choice of cases and
controls
Cross-sectional study—Give the eligibility criteria, and the
sources and methods of selection of participants
(b) Cohort study—For matched studies, give matching
criteria and number of exposed and unexposed
Case-control study—For matched studies, give matching
criteria and the number of controls per case
Variables 7 Clearly define all outcomes, exposures, predictors, potential
confounders, and effect modifiers. Give diagnostic criteria, if
applicable
Data sources/
measurement
8* For each variable of interest, give sources of data and details
of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than
one group
Bias 9 Describe any efforts to address potential sources of bias
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Study size 10 Explain how the study size was arrived at
Quantitative variables 11 Explain how quantitative variables were handled in the
analyses. If applicable, describe which groupings were
chosen and why
Statistical methods 12 (a) Describe all statistical methods, including those used to
control for confounding
(b) Describe any methods used to examine subgroups and
interactions
(c) Explain how missing data were addressed
(d) Cohort study—If applicable, explain how loss to follow-
up was addressed
Case-control study—If applicable, explain how matching of
cases and controls was addressed
Cross-sectional study—If applicable, describe analytical
methods taking account of sampling strategy
(e) Describe any sensitivity analyses
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg
numbers potentially eligible, examined for eligibility, confirmed
eligible, included in the study, completing follow-up, and analyzed
(b) Give reasons for non-participation at each stage
(c) Consider use of a flow diagram
Descriptive data 14* (a) Give characteristics of study participants (eg demographic,
clinical, social) and information on exposures and potential
confounders
(b) Indicate number of participants with missing data for each
variable of interest
(c) Cohort study—Summarize follow-up time (eg, average and total
amount)
Outcome data 15* Cohort study—Report numbers of outcome events or summary
measures over time
Case-control study—Report numbers in each exposure category, or
summary measures of exposure
Cross-sectional study—Report numbers of outcome events or
summary measures
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted
estimates and their precision (eg, 95% confidence interval). Make
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clear which confounders were adjusted for and why they were
included
(b) Report category boundaries when continuous variables were
categorized
(c) If relevant, consider translating estimates of relative risk into
absolute risk for a meaningful time period
Other analyses 17 Report other analyses done—eg analyses of subgroups and
interactions, and sensitivity analyses
Discussion
Key results 18 Summarize key results with reference to study objectives
Limitations 19 Discuss limitations of the study, taking into account sources of
potential bias or imprecision. Discuss both direction and magnitude
of any potential bias
Interpretation 20 Give a cautious overall interpretation of results considering
objectives, limitations, multiplicity of analyses, results from similar
studies, and other relevant evidence
Generalizability 21 Discuss the generalizability (external validity) of the study results
Other information
Funding 22 Give the source of funding and the role of the funders for the present
study and, if applicable, for the original study on which the present
article is based
*Give information separately for cases and controls in case-control studies and, if applicable,
for exposed and unexposed groups in cohort and cross-sectional studies.
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