Open access
Prevalence of myocardial fibrosis among
To cite: Shoar S, Dao CD,
Higgason NM, et al. Prevalence
of myocardial fibrosis among
patients living with HIV and
factors associated with a
higher prevalence rate: protocol
for a systematic review and
meta-­analysis. BMJ Open
2023;13:e067350. doi:10.1136/
bmjopen-2022-067350
► Prepublication history and
additional supplemental material
for this paper are available
online. To view these files,
please visit the journal online
(http://dx.doi.org/10.1136/​
bmjopen-2022-067350).
Received 18 August 2022
Accepted 22 February 2023
© Author(s) (or their
employer(s)) 2023. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
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BMJ.
1
Department of Clinical
Research, Scientific
Collaborative Initiative, Largo/
Houston, MD/TX, USA
2
School of Medicine, McGovern
Medical School, University of
Texas Health Science Center at
Houston, Houston, Texas, USA
3
Department of Medicine,
Kashan University of Medical
Sciences, Kashan, Isfahan, Iran
(the Islamic Republic of)
Correspondence to
Dr Nasrin Shoar;
​nasrinshoar@​gmail.c​ om
patients living with HIV and factors
associated with a higher prevalence rate:
protocol for a systematic review and meta-­
analysis
Saeed Shoar  ‍ ‍,1 Calvin D Dao,2 Noel M Higgason,2 Nasrin Shoar  ‍ ‍3
ABSTRACT
Introduction  HIV infection is an established risk factor
for the development of cardiovascular diseases. Although
increasing evidence implicates a higher prevalence of
myocardial fibrosis (MF) among patients living with HIV
(PLWH) compared with the HIV-­negative population, there
is a paucity of knowledge regarding its determinants and
factors associated with higher odds of MF development.
We aim to perform a systematic review to estimate the
prevalence of MF among PLWH. Additionally, we will
determine the factors associated with higher odds of MF
among PLWH compared with the HIV-­negative population.
Methods  A systematic review will be performed by
consulting the Cochrane handbook for systematic reviews
of interventional studies reporting a confirmed diagnosis
of MF among PLWH. Articles will be eligible if they provide
the prevalence of MF among PLWH and HIV-­negative
populations or the odds ratio (OR) and 95% confidence
interval (CI) of MF development in relation to HIV.
Depending on the quality of the data and the heterogeneity
among the included studies, a random-­effects or fixed-­
effects model will be used to pool and compare the ORs
of MF among PLWH and HIV-­negative population. Factors
associated with higher odds of MF in relation to HIV will
also be determined.
Ethics and dissemination  Ethical approval and obtaining
informed consent are not required for this systematic
review as it does not use individual patients’ data. Results
of this study will be published in a peer-­reviewed medical
journal.
INTRODUCTION
Infection with HIV is a risk factor for the
development of coronary artery disease,
heart failure,1 2 arrhythmia3–6 and ischaemic
stroke.7–9 Additionally, the prevalence of
cardiac abnormalities is reportedly higher
in patients living with HIV (PLWH) than in
the normal population.3 10–12 Postmortem
studies have indicated a higher prevalence
of cardiomyopathy and myocardial fibrosis
(MF) among PLWH than among the HIV-­
negative population.6 12 Although the higher
Shoar S, et al. BMJ Open 2023;13:e067350. doi:10.1136/bmjopen-2022-067350
Protocol
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STRENGTHS AND LIMITATIONS OF THIS STUDY
⇒ A meta-­analysis on this topic will provide a better
estimate of the prevalence of myocardial fibrosis
among patients living with HIV.
⇒ Due to the potential variability in the methodologies
of eligible studies, data will be heterogeneous and
difficult to interpret.
⇒ Eligible studies will be stratified based on their level
of evidence to mitigate potential heterogeneities in
the literature during data analysis.
⇒ Exclusion of non-­English studies will introduce lan-
guage bias to this systematic review.
rate of cardiovascular diseases among PLWH
has been contributed to a higher prevalence
of traditional risk factors and metabolic
derangements,13 14 the relative risk remains
significant after adjusting for these covariates
and considering the use of modern antiret-
roviral therapy (ART) with fewer metabolic
adverse effects.
MF is reportedly a prevalent finding in
postmortem studies of patients with sudden
cardiac death (SCD).15 However, the majority
of patients with SCD who are found to have
MF were asymptomatic or showed non-­
specific symptoms before death.6 15 Emerging
evidence indicates that subclinical myocar-
dial inflammation and fibrosis are prevalent
findings among PLWH.6 12
Aim
As MF substantially increases the risk of SCD
along with other clinically significant elec-
trocardiographic abnormalities, we aimed to
perform a systematic review of the published
literature to estimate the prevalence of devel-
oping MF in relation to HIV and identify
factors associated with a higher prevalence
rate among PLWH.
1
Open access
Rationale
PLWH are reportedly predisposed to coronary artery and
other atherosclerotic cardiovascular diseases. Addition-
ally, radiological and histological studies have shown a
higher detection rate for MF among PLWH than among
HIV-­negative population. As the risk of SCD increases
with the existence and extent of MF among PLWH and
their HIV-­negative counterparts, a systematic review of
the literature is needed to quantify this risk.
METHODS
Study design
A systematic review will be conducted by consulting the
Cochrane handbook for systematic reviews of interven-
tions16 and will be reported according to the preferred
reporting checklist for meta-­ analysis of observational
studies in epidemiology.17 We aim to identify human
studies in the English language that provide original data
on PLWH who have been diagnosed with MF (online
supplemental file 1). Original data will be defined as
no synthesis of literature data or reanalysis of previ-
ously published results. The protocol for this systematic
review has been registered with the Open Science Frame-
work with the following digital object identifier (DOI):
10.17605/OSF.IO/7UPBK.
Review questions
What is the prevalence of MF among PLWH and what
factors increase the odds of MF among PLWH compared
with HIV-­negative population? The review questions have
been specified further in online supplemental file 1.
Search strategy
Two investigators will independently review the literature
available online in the following databases: MEDLINE/
PubMed, EMBASE/Ovid, Web of Science and Google
Scholar from inception to 31 December 2022. A combi-
nation of the following search terms reflecting the review
questions will be used: “cardiac fibrosis”, “myocardial
fibrosis”, “endomyocardial fibrosis” and “HIV” or “human
immunodeficiency virus”. The precise search strategy is
presented in online supplemental file 2 for MEDLINE/
PubMed. This strategy will be modified for each other
databases by consulting an experienced librarian with
expertise in biomedical literature review.
The bibliography of relevant articles and key journals in
the fields of HIV, infectious diseases, cardiology, cardio-
vascular diseases and radiology will be manually searched
to identify additional literature. Owing to the uncertainty
of the quality of grey literature, it will not be taken into
consideration in this systematic review.
The titles and abstracts of the articles retrieved through
these searches will be screened for their relevance. There-
after, the full text of the relevant articles will be retrieved
to ensure eligibility. Any discrepancies in the selection
of studies will be resolved by discussion with a senior
investigator.
2 Shoar S, et al. BMJ Open 2023;13:e067350. doi:10.1136/bmjopen-2022-067350
BMJ Open: first published as 10.1136/bmjopen-2022-067350 on 14 March 2023. Downloaded from http://bmjopen.bmj.com/ on March 15, 2023 by guest. Protected by copyright.
Figure 1  PRISMA flow chart demonstrating a systematic
approach for the literature review and study selection.
PRISMA: Preferred Reporting Items for Systematic
Reviews and Meta-­Analysis
The step-­by-­step approach to the screening and selec-
tion of eligible studies will follow the Preferred Reporting
Items for Systematic Reviews and Meta-­Analysis (PRISMA)
and is depicted in the PRISMA flow chart (figure 1). This
approach will be implemented for all the online data-
bases, as well as for the manual search of other references.
The literature review process will be repeated prior to the
pooling of data to ensure the identification and inclusion
of more recent publications.
Study eligibility
Studies will be included in this systematic review if they
meet all the following inclusion criteria:
1. Full text is accessible in English language.
2. Original data on adults (age ≥18 years) with HIV
(PLWH) is provided.
3. A diagnosis of MF has been established in the study
participants using a universally accepted diagnostic
modality, such as cardiac MRI or biopsy.
4. The frequency of MF among PLWH and HIV-­negative
population, or the odds ratio (OR) and 95% confi-
dence interval (CI) of developing MF in relation to
HIV has been provided.
Studies will be excluded if they meet any of the following
exclusion criteria.
1. Original data on the concept of MF among PLWH is
not provided; the paper is a review article or reanalysis
of previously published datasets; and editorial or com-
mentaries without any original data.
2. Diagnosis of HIV infection or MF is a presumption and
has not been confirmed based on the standard-­of-­care
diagnostic modality.
3. Full text is not available or cannot be obtained in En-
glish language.

4. Case reports or single-­arm studies with inherent meth-
odological limitations in estimating the OR for the de-
velopment of MF among PLWH.
Data extraction
After full texts of the eligible studies have been
obtained and stored in a shared drive, two investigators
will read and extract data from these articles. Data on
the variables of interest will be entered into a prede-
signed online spreadsheet for further evaluation.
A third investigator will oversee the data extraction
process to ensure accuracy and consistency. In case of
missing data, an attempt will be made to contact the
senior author of the study in question.
The following data will be collected: patients’ demo-
graphics (age, sex and race/ethnicity), socioeco-
nomic status (educational level, household income,
and geographic region), medical conditions (comor-
bidities, coexisting clinical conditions, prescribed
medications, antiretroviral therapy [ART] regimen,
environmental and/or occupational exposures, nutri-
tional status and lifestyle features), features of MF
(time from diagnosis of HIV to the diagnosis of MF,
time from initiation or latest change of ART to the
diagnosis of MF, diagnostic modality for MF, histolog-
ical studies if available and other cardiovascular diag-
nostic information).
Quality assessment
The quality of the included studies will be assessed
at the time of data extraction by two independent
investigators, using the Newcastle-­ O ttawa Scale 18
19
and mixed-­m ethods appraisal tools. These quality
assessment tools are appropriate for the nature of the
studies, which primarily comprises non-­randomised
and observational studies. Although no study will be
excluded from this systematic review based on quality
assessment, the quality score will be reflected in the
results of the data synthesis.
Meta-analysis
The extracted data will be curated for narrative
synthesis and qualitative appraisal by the senior
author. If sufficient data are available on the frequency
of MF among PLWH and HIV-­n egative population,
a meta-­regression analysis will be conducted after
adjusting for confounders, such as ART, to deter-
mine the OR and 95% CI of MF in relation to HIV.
Furthermore, factors associated with higher odds of
MF will be compared between those who developed
the condition and those who did not among PLWH. If
the OR for developing MF has been provided, a meta-­
analysis will be performed to estimate the pooled
OR and 95% CI, using either a random-­e ffects model
for high-­heterogeneity data or a fixed-­e ffects model
for medium-­ to-­
low heterogeneity data. Statistical
heterogeneity among studies will be assessed using
the I2 statistic. I2<30%, 30%<I2<60 and I2>60% will
Shoar S, et al. BMJ Open 2023;13:e067350. doi:10.1136/bmjopen-2022-067350
Open access
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be classified as low, medium and high heterogeneity,
respectively.
Subgroup analysis
The included studies will have used different diagnostic
modalities to diagnose MF. Hence, we will attempt to
stratify the patient population based on diagnostic modal-
ities to avoid any potential bias in the estimated odds ratio
of MF development among PLWH compared with HIV-­
negative patients.
Statistical tools
Statistical analyses will be performed using STATA (V.16;
StataCorp). Results will be considered statistically signifi-
cant when the OR and 95% CIs does not include the null
value of 1 or the p value is <0.05. Forest plots will be used
to visualise the results of the meta-­analysis on the esti-
mated pooled ORs and 95% CIs. If more than 10 studies
are available, a funnel plot will be constructed to demon-
strate potential publication bias.
Patient and public involvement
No patients will be directly involved in this study.
DISCUSSION
A significantly higher prevalence of cardiac diseases is
seen among PLWH than among the HIV-­negative popu-
lation.6 12 However, the clinical outcomes associated with
HIV-­related cardiomyopathy vary based on the extent of
cardiac involvement. Moreover, the underlying mecha-
nisms through which HIV affects the heart remain largely
unexplained.
In a comparative observational study of 47 HIV-­
positive and 21 HIV-­ n egative individuals, Yan et al
evaluated myocardial structure and function using a
comprehensive, multiparametric, cardiac MR (CMR)
scan protocol. 12 PLWH had significantly lower left and
right systolic functions than did HIV-­n egative controls.
Additionally, late gadolinium enhancement suggestive
of MF was detected in 21.95% of HIV-­p ositive patients,
compared with none in HIV-­n egative patients. Factors
associated with higher odds of MF development,
as detected on CMR, included progression to AIDS
(OR: 6.3), HIV duration >5 years (OR: 4.3), age >40
years (OR: 2.4), CD4+ cell count <500 cells/mm3 (OR:
1.84) and viral load (plasma HIV RNA) >75 copies/
mL (OR: 1.6). Another study by Tseng et al used post-
mortem data of 108 PLWH who had out-­of-­hospital
cardiac arrests (61 non-­S CDs and 47 SCDs) and found
a significantly higher fibrosis burden (mean percent
fibrosis) in the interstitial myocardium and perivas-
cular tissue of PLWH than in HIV-­n egative patients.6
Although the proportion of arrhythmia-­induced SCD
was similar between the HIV-­p ositive and HIV-­negative
patients (47% vs 56%), drug overdose was significantly
higher among PLWH (34% vs 13%). This suggests
that although chronic inflammation in HIV infection
3
 Open access
might provide a susceptible environment for fibrosis
development, major cardiovascular events arise due to
other behavioural and metabolic risk factors.
Many studies on PLWH who present with cardiovas-
cular events have a retrospective design, small sample
size and lack comprehensive data on the underlying
mechanisms for the development of different cardio-
vascular manifestations. This systematic review aims to
narrow the knowledge gap between HIV diagnosis and
accelerated occurrence of cardiovascular diseases,
especifically MF. Additionally, MF is most likely under-­
reported in the literature among PLWH and HIV-­
negative individuals. However, we expect that the OR
of developing MF is proportionally affected by this
under-­reporting.
Ethics and dissemination
Ethical approval and obtaining an informed consent
are not required for this systematic review as it does not
use identifiable data of individual patients. Results of
this study will be published in a peer-­reviewed medical
journal.
Contributors  SS: study design, literature review, drafting of the manuscript,
final revision of the manuscript for intellectual changes. CDD: literature review,
drafting of the manuscript, final revision of the manuscript for intellectual changes.
NMH: literature review, drafting of the manuscript, final revision of the manuscript
for intellectual changes. NS: study design, literature review, final revision of the
manuscript for intellectual changes.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient and public involvement  Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication  Not applicable.
Provenance and peer review  Not commissioned; externally peer reviewed.
Supplemental material  This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access  This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
4 Shoar S, et al. BMJ Open 2023;13:e067350. doi:10.1136/bmjopen-2022-067350
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properly cited, appropriate credit is given, any changes made indicated, and the use
is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iDs
Saeed Shoar http://orcid.org/0000-0002-7000-0511
Nasrin Shoar http://orcid.org/0000-0002-3321-2646
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