bmj open · for peer review only 2 risk of bias in individual studies 12 describe methods used for...

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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1

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*

([email protected])

Jobert Richie N. Nansseu3, 4

([email protected])

Lewis N. Um5 ([email protected])

Steve Raoul N. Noumegni5 ([email protected])

Paule Sandra D. Simé5 ([email protected])

Jean Jacques N. Noubiap6, 7

([email protected])

Sinata Koulla-Shiro5, 8

([email protected])

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:

[email protected]

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

sheet N°360 2015 July 2015. http://www.who.int/mediacentre/factsheets/fs360/en/. 14

2. UNAIDS. 2014 Global Statistics. Secondary 2014 Global Statistics 2014. 15

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

Suppl):D34-41. 20

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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diseases in the combination antiretroviral therapy era. American journal of respiratory 2

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7. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension. 4

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of an existing tool and evidence of interrater agreement. Journal of clinical 10

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10. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of 12

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11. Cochran GW. The Combination of Estimates from Different Experiments. Biometrics 15

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15. Makubi A, Hage C, Lwakatare J, et al. Contemporary aetiology, clinical characteristics 23

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16. Bakari M, Chillo P, Lwakatare J. Factors associated with, and echocardiographic findings 26

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Salaam, Tanzania. Tanzania journal of health research 2013;15(2):73-81. 28

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19. Menanga AP, Ngomseu CK, Jingi AM, et al. Patterns of cardiovascular disease in a group 35

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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

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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

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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

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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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2

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


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




Keywords: Pulmonary hypertension, Pulmonary arterial hypertension, HIV & AIDS < INFECTIOUS DISEASES, Africa, Review


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1

Prevalence and incidence of pulmonary hypertension among HIV-infected

people in Africa: a systematic review and meta-analysis


([email protected])


([email protected])




Leopold N. Amindé6, 7

([email protected])


([email protected])


([email protected])






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


9Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape

Town, South Africa




[email protected]

Keywords

Pulmonary arterial hypertension, pulmonary hypertension, HIV, AIDS, Africa

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Abstract


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.


Participants: African HIV-infected people residing inside Africa.

Outcome: Prevalence and incidence of PH diagnosed through echocardiography or right


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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• Only 3 studies were eligible from only two regions in Africa.


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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5

Introduction



of 2014, with 2.0 million people becoming newly infected worldwide; what’s worse, 1.2



accounts for almost 70% of the global HIV new infections.1 2


mmHg on right heart catheterization at rest.3 4

The classification of PH includes: pulmonary


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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6

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 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,



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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7

- We considered all published and unpublished studies reported from 1st January 1980 to 30

June 2016. No language restriction was applied.

Exclusion criteria



- 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.


review




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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8

conducted in PubMed is shown in S2 Appendix. This search strategy was adapted to fit with

other databases.



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).







that the selection criteria were reliably applied by all review authors.


Two investigators (JJRB and LNU) independently extracted data pertaining to general



PH, antiretroviral therapy), prevalence and/or incidence of PH. Where only primary data



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9




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 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


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10

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).



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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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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12


studies. These studies had a moderate risk of bias (Table 2). 2


STROBE quality of reporting* Risk of bias by Hol et al. £

Score range, 0

to 22


0 to 10

Interpretation


quality

7 Moderate risk

Menanga, 2015 20

19 Good/fair

quality

7 Moderate risk

Sliwa, 2012 19

19 Good/fair

quality

6 Moderate risk


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


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


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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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



10




14



17

References 18





en.pdf. 23

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Suppl):D34-41. 3

4. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary 4


Suppl):D42-50. 6



Res Ther 2015;12:36. 9



2015;45(5):515-28. 12









10. Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: 21

modification of an existing tool and evidence of interrater agreement. Journal of 22

clinical epidemiology 2012;65(9):934-9. 23





Bmj 2003;327(7414):557-60. 28

13. Barendregt JJ, Doi SA, Lee YY, et al. Meta-analysis of prevalence. J Epidemiol 29

Community Health 2013;67(11):974-8. 30


1954;10(1):101-29. 32


medicine 2002;21(11):1539-58. 34





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18


52. 2



9. 5




2012;33(7):866-74. 9



2015;5(6):420-7. 12






2012;26(11):1387-92. 18


Chest 1991;100(5):1268-71. 20





reviews 2003;5(4):195-204. 25




20, v. 29



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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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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1



TITLE 1


ABSTRACT 2-3


2-3

INTRODUCTION 5-6



6

METHODS 6-9


6




7-8


8




8


8

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2



9



(e.g., I2) for each meta-analysis. 9


9


9

RESULTS 9-12


10


10-11



11-12




DISCUSSION 13-15


13


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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16

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1


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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1





(High risk)

External Validity




target population?




Internal Validity




hypertension used?










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Item

No Recommendation





Introduction




hypotheses

Methods




collection







controls









applicable

Data sources/

measurement




one group


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2




chosen and why




interactions



up was addressed






Results








confounders




amount)


measures over time




summary measures



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3


included


categorized





Discussion









Other information



article is based



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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


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




Keywords: Pulmonary arterial hypertension, Pulmonary hypertension, HIV, AIDS, Africa


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1

Prevalence and incidence of pulmonary hypertension among HIV-infected

people in Africa: a systematic review and meta-analysis


([email protected])


([email protected])




Leopold N. Amindé6, 7

([email protected])


([email protected])


([email protected])






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


9Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape

Town, South Africa




[email protected]

Keywords

Pulmonary arterial hypertension, pulmonary hypertension, HIV, AIDS, Africa

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Abstract


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.


Participants: African HIV-infected people residing inside Africa.

Outcome: Prevalence and incidence of PH diagnosed through echocardiography or right


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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• Only 3 studies were eligible from three of the five sub-regions of Africa.


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



of 2014, with 2 million people becoming newly infected worldwide; what’s worse, 1.2



accounts for almost 70% of the global HIV new infections.1 2


mmHg on right heart catheterization at rest.3 4

The classification of PH includes: pulmonary


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 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,



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 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.


review.




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.



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).







that selection criteria were reliably applied by all review authors. Agreement was measured

using the Kappa statistic.10


Two investigators (JJRB and LNU) independently extracted data pertaining to general



PH, antiretroviral therapy), prevalence and/or incidence of PH. Where only primary data


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Agreement was measured using the Kappa statistic.10


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 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


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).



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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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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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


STROBE quality of

reporting*

Risk of bias by Hoy et al. £

Score range,

0 to 22


0 to 10

Interpretation


quality

7 Moderate risk

Menanga, 2015 21

19 Good/fair

quality

7 Moderate risk

Sliwa, 2012 20

19 Good/fair

quality

6 Moderate risk


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


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


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


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



11




15



18

References 19



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