Extended-spectrum β-lactamase-producing Enterobacterales among people living with human immunodeficiency virus across the globe: A systematic review and meta-analysis

Mitkie Tigabie; Abebe Birhanu; Muluneh Assefa; Getu Girmay; Kebebe Tadesse

doi:10.1371/journal.pone.0321873

. 2025 Jun 10;20(6):e0321873. doi: 10.1371/journal.pone.0321873

Extended-spectrum β-lactamase-producing Enterobacterales among people living with human immunodeficiency virus across the globe: A systematic review and meta-analysis

Mitkie Tigabie ^1,^*, Abebe Birhanu ¹, Muluneh Assefa ¹, Getu Girmay ², Kebebe Tadesse ³

Editor: Amir Nutman⁴

PMCID: PMC12151346 PMID: 40493608

Abstract

Background

People living with HIV are vulnerable to antibiotic-resistant bacterial infections because of frequent healthcare visits, the consumption of many antimicrobials, and the weakened immune system to fight infections. Our objective was to provide comprehensive data about ESBL-producing Enterobacterales among HIV-positive individuals across the globe.

Methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. To select eligible articles published between January 1, 2010, and May 12, 2024, a literature search was performed on available electronic databases such as PubMed, Hinari, Google Scholar, and Scopus. The quality of the included studies was assessed via the Joanna Briggs Institute critical appraisal tool. The data were extracted from the eligible studies via Microsoft Excel 2019 and analyzed via STATA version 17. A random effects model was constructed via the DerSimonian and Laird method. The heterogeneity was checked through the Cochrane Q statistic, and the magnitude was quantitatively measured via I² statistics. To determine the possible sources of heterogeneity, a subgroup analysis was performed. Additionally, a sensitivity analysis was conducted, and publication bias was checked via funnel plots and Egger’s regression tests. A p value of less than 0.05 was considered evidence of heterogeneity and small study effects according to the Cochrane Q statistic and Egger’s test, respectively. The protocol was registered previously (PROSPERO ID: CRD42024557981).

Results

A total of 5305 HIV-positive individuals from 20 studies were included in our meta-analysis. The overall pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals was 20.30% (931/5305; 95% CI: 15.13–25.47%, P < 0.001), with a high level of heterogeneity (I² = 97.82%, P < 0.001). The predominant ESBL producers were K. pneumoniae, with a pooled prevalence of 40.84% (76/217; 95% CI: 26.87–54.81%), followed closely by E. coli at 40.14% (348/985; 95% CI: 27.83–52.45%). In the subgroup analysis, the highest magnitude of ESBL-producing pathogens was observed in Asia (195/715; 28.55%), followed by Africa (666/3981; 19.12%). Additionally, the highest pooled prevalence of ESBL-producing pathogens among HIV-positive individuals was reported to be colonization 23.78% (613/2455; 95% CI: 15.36–32.19, I² = 96.78%, p < 0.001), followed by infection 15.77% (318/2850; 95% CI: 10.06–21.49, I² = 97.45%, p < 0.001). Among the different types of ESBL enzyme-encoding genes, bla_CTX-M was the most common (73 out of 150 isolates, 48.7%), followed by bla_TEM (49 out of 150, 32.7%).

Conclusion and recommendations

This study demonstrated that HIV-positive individuals are commonly colonized and infected with ESBL-producing Enterobacterales. The highest prevalence of these pathogens was reported in Asia and Africa. To reduce mortality from severe bacterial infections in HIV patients, resources should be distributed equitably across all regions. Particular attention should be given to high-prevalence areas, where early detection of colonization and infection with antibiotic-resistant pathogens is critical. Enhanced surveillance of ESBL-producing organisms among HIV-positive individuals is also strongly recommended.

Introduction

Antimicrobial resistance (AMR) is one of the top ten threats to global public health, and it is a major and serious issue in the 21st century [1]. Recent studies have provided updated insights into the global impact of antimicrobial resistance (AMR). In 2021, approximately 1.14 million deaths were directly attributable to bacterial AMR, with a total of 4.71 million deaths associated with AMR worldwide [2]. Projections indicate that, without significant intervention, AMR could be responsible for up to 10 million deaths annually by 2050 [3]. Regionally, the World Health Organization (WHO) African Region experiences a significant impact, with approximately 250,000 deaths attributable to bacterial AMR infections [4]. In the European region, about 133,000 deaths are attributed to bacterial AMR infections [5].

Although the overuse and misuse of antimicrobials in humans, animals and their environments are the main factors that increase AMR, limited AMR surveillance and poor infection prevention and control practices also contribute to the increase in AMR infections [6]. Furthermore, immunosuppressive conditions such as human immunodeficiency virus (HIV) infection create favorable conditions for the development of bacterial resistance. People living with HIV are more likely to have contact with healthcare facilities and be exposed to invasive medical procedures than the general population is. Moreover, these populations are vulnerable to bacterial AMR infections due to frequent hospital admissions, the consumption of many antimicrobial agents, and the weakened immune system to fight infections [7,8]. Additionally, antibiotic prophylaxis for the prevention of opportunistic infections among HIV patients is the major factor contributing to the development of resistance [9].

Human immunodeficiency virus remains a major global public health concern, with a significant burden in many low- and middle-income countries. As of 2023, an estimated 39.9 million people were living with HIV worldwide, and approximately 630,000 deaths were attributed to HIV-related causes. The cumulative number of individuals living with HIV has continued to rise, reaching an estimated 42.3 million to date. This persistent and widespread prevalence of HIV not only presents challenges for disease management and health systems but also has important implications for other infectious diseases, particularly in relation to antimicrobial resistance [10].

Acquired immunodeficiency syndrome (AIDS) occurs at the most advanced stage of HIV infection, and in this stage, people can also develop not only opportunistic infections such as tuberculosis, pneumocystis pneumonia and cryptococcal meningitis but also severe bacterial infections [11,12]. These severe bacterial infections are caused by common bacterial pathogens that are grouped under gram-positive cocci and gram-negative bacilli [12]. Among bacterial pathogens, Enterobacterales are multidrug resistant owing to their ability to produce various resistance mechanisms, including efflux pumps, porin modification, overexpression, and enzyme production [13]. Enzymatic inactivation due to extended-spectrum β-lactamase (ESBL) enzyme production is the predominant cause of resistance to β-lactam antibiotics [13,14]. These enzymes can hydrolyze penicillins, cephalosporins, and aztreonam. Penicillins and cephalosporins are widely accessible and frequently used to treat various infections globally, especially in developing countries. [14].

Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) are the predominant Enterobacterales that produce ESBL enzymes [14,15]. Infections with these pathogens increase the risk of treatment failure and have led to increased use of last-resort antibiotics such as carbapenems [16] and combination therapies with more toxic antibiotics such as polymyxin, which cause nephrotoxicity, ototoxicity, and neuromuscular blockade [17].

To improve the management of HIV-positive patients and reduce mortality due to complications with bacterial infections, comprehensive data concerning resistant bacteria due to ESBL enzyme inactivation of antibiotics are paramount. Nevertheless, on the basis of previous studies, the proportion of ESBL-producing Enterobacterales among HIV-positive individuals varies from 2.3% to 57.4% [18,19]. In addition, there is a great discrepancy in the prevalence of ESBL-producing Enterobacterales among HIV-positive individuals in previously published studies [19–31].

Moreover, most existing systematic reviews and meta-analyses on HIV-related infections have focused on multidrug-resistant Mycobacterium tuberculosis [32] and methicillin-resistant Staphylococcus aureus [33]. However, pooled data on ESBL-producing Enterobacterales among HIV-positive individuals are still lacking. Therefore, this systematic review and meta-analysis aimed to provide comprehensive data concerning ESBL-producing Enterobacterales among HIV-positive individuals across the globe.

Methods

Study design and protocol registration

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (SF 1 Table). The protocol is available on the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42024557981).

Search strategy

Two authors (MT, KT) searched the Medline/PubMed, Hinari, Google Scholar, and Scopus electronic databases for studies published from 1 January 2010–12 May 2024. We used keywords alone and in combination with Boolean operators such as “OR” or “AND”. For example, articles were identified via MeSH terms from keywords of the title on Medline/PubMed, as follows (((((((antimicrobial resistance) OR (antibiotic resistance)) OR (multidrug resistance)) OR (extended-spectrum β-lactamase)) OR (ESBL)) AND (((((((gram-negative) OR (bacteria)) OR (bacilli)) OR (enterobacteriaceae)) OR (enterobacterales)) OR (Escherichia coli)) OR (Klebsiella pneumoniae))) AND (((((immunocompromised host) OR (human immunodeficiency virus)) OR (acquired immunodeficiency syndrome)) OR (HIV)) OR (HIV/AIDS))) AND (“2010/01/01” to “2024/05/12”).

Outcome of interest

The main outcome was the prevalence of ESBL-producing Enterobacterales among people living with HIV across the globe. We estimated the prevalence by dividing the number of ESBL-producing Enterobacterales cases by the total sample size. For case-control studies, the prevalence was calculated only among the cases. The prevalence of ESBL-producing bacteria for individual species was calculated by dividing the number of ESBL-producing isolates by the total number of isolates for that specific species.

Eligibility criteria

We used the CoCoPop (Condition, Context, and Population) approach, in which the prevalence of ESBL-producing Enterobacterales was considered the condition (CO), people living with HIV were considered the population (POP), and the world served as the context (CO). To identify eligible articles, we declared the predetermined inclusion and exclusion criteria; all cross-sectional, case‒control, and cohort studies reported ESBL-producing Enterobacterales among people living with HIV worldwide. The review included studies with mixed populations which reported on ESBL-producing Enterobacterales prevalence by HIV status. Studies published between January 1, 2010, and May 12, 2024, which were written exclusively in the English language, and studies that were peer reviewed were included in this systematic review and meta-analysis. However, systematic reviews and meta-analyses, case reports, case series, conference papers and pilot studies were excluded. Preprint studies were also excluded.

Quality assessment

Three reviewers (MT, KT, and AB) independently and in duplicate screened the titles and abstracts of the studies and subsequently assessed the potential eligibility of the relevant full texts on the basis of the predefined inclusion criteria. The quality of studies was assessed via standard critical appraisal tools prepared by the Joanna Briggs Institute (JBI) for prevalence and case‒control studies [34]. The JBI appraisal checklist contains 9 and 10 questions for cross-sectional and case‒control studies, respectively. These critical appraisal tools have yes, ‘no’, ‘unclear’, and ‘not applicable’ options. For each question, a score of 0 was assigned for ‘no’, ‘unclear’, and ‘not applicable’ and a score of 1 was assigned for ‘yes’. The discrepancies were solved by taking the average score. The total score is calculated by counting the number of “yes” in each row. On the basis of the score of the quality assessment tool, the highest score had the minimum risk of bias. Overall scores ranging from 0–4, 5–6, and 7–9 for prevalence studies and from 0–4, 5–7, and 8–10 for case‒control studies are declared high, moderate, and low risk of bias, respectively [35]. Finally, studies with a score of five and above for “yes” (have moderate and low risk of bias) were included in the systematic review and meta-analysis (SF 2 Table).

Data extraction

All of the studies obtained from different electronic databases were combined and properly exported to EndNote version 9.2 (Clarivate Analytics, Philadelphia, PA, USA). Then, the articles were merged into one folder for identification, duplicate articles were removed, and the quality of the studies was checked. We subsequently assessed the eligibility of the studies imported into Microsoft Excel 2019 (Microsoft Corp., Redmond, WA, USA).

All important parameters were extracted from each study by three authors (MT, KT, & AB.) independently. Discrepancies between them were resolved by consensus. The data extraction format was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. For each study, the primary author, year of publication, sample size, study design, study year, study country, age group, investigation type (phenotype or genotype), status (infection or colonization) and methods of detection for ESBL were extracted. Furthermore, data on the total number of ESBL-producing isolates, individual ESBL-producing species, and their corresponding total number of isolates were extracted.

Statistical analysis

The extracted data were exported to STATA software version 17 for analysis. We conducted a meta-analysis via the random effects DerSimonian and Laird model to estimate the pooled prevalence and 95% confidence intervals (CIs) [36]. The presence of between-study heterogeneity was checked by using the Cochrane Q statistic. The magnitude of heterogeneity between the included studies was quantitatively measured by the inverse variance (I² statistic). I² = 0, I²= 0–25%, I² = 50–75%, and I² > 75% indicate no, low, moderate, and high heterogeneity, respectively. The significance of heterogeneity was determined by the p value of the Cochrane Q statistic, and a p value of less than 0.05 was evidence of heterogeneity [37]. The possible sources of heterogeneity were further investigated by performing a subgroup analysis in reference to the continents, publication year, age categories, and methods of confirmation for the ESBL. Additionally, a sensitivity analysis was conducted to determine the influence of single studies on the pooled estimates. Publication bias was checked by using a funnel plot test graphically and more objectively through Egger’s regression tests. A statistically significant Egger’s test (P value < 0.05) indicates the presence of a small study effect [38].

Results

Study selection and identification

We identified a total of 1478 articles from available scientific databases such as PubMed, Hinari, Google Scholar, and Scopus. Of these, 997 studies were removed because they were duplications. Four hundred eighty-one studies were screened by reading their titles and abstracts. Two hundred forty-six articles were removed due to unrelated topics, incorrect publication periods, mixed or non-human populations, or inclusion of non-Enterobacterales or other pathogens. After that, 235 articles were screened by reading their full texts, and 198 studies were excluded because they were pilot studies, preprints, or involved study participants other than HIV patients. Thirty-seven studies passed the eligibility assessment, but 17 articles were removed because the outcomes were not reported or did not fulfill the quality criteria. Finally, 20 studies were eligible and included in the final meta-analysis [18–21,23–31,39–45], as presented in the PRISMA flow diagram (Fig 1).

Summary of the risk of bias results

Out of the thirty-seven studies that passed the eligibility assessment, 11 were excluded because they did not meet the quality criteria. Among the studies that met the quality criteria, 13 out of 20 (65.0%) had a low risk of bias, while 7 (35.0%) had a moderate risk of bias. Six studies were excluded due to a high risk of bias (see SF 2 Table).

Characteristics of the studies included in the systematic review and meta-analysis

Among the included studies, 15 (75.0%) studies were published in and after 2020 [18–21,23–28,39,40,43–45]. Eighteen (90.0%) studies were cross-sectional [18–21,23–31,39,40,43–45], whereas the remaining two studies were case‒control studies [30,41]. Eleven (55.0%) studies focused on colonization [20,21,23,24,28–30,39,42,43,45], whereas the remaining 9 studies focused on infection [18,19,25–27,31,40,41,44]. All of the studies included in this review were from three continents: Africa [18,20–23,25,27,29,31,39,40,43–45], Asia [19,26,28,30,41], and Europe [24,42] (Table 1).

Table 1. Characteristics of individual studies included in the meta-analysis of ESBL-producing Enterobacterales among HIV-positive individuals across the globe, 2024.

Study (Author, Year)	Study Year	Country	Design	Sample size	Specimen type	Age group	Status	Inv. M^*	Meth^**	ESBL case N (%)
Bayleyegn et al, 2021 [39]	2020	Ethiopia	CS	161	Stool	Children	Colonization	P	CDT	32 (19.9)
Dimani et al, 2023 [20]	2021	Cameroon	CS	185	Stool and rectal swabs	All age	Colonization	P&G	DDST	61 (32.9)
Endalamaw et al, 2020 [18]	2017	Ethiopia	CS	387	Urine	All age	Infection	P	DDST	9 (2.3)
Falodun et al, 2021 [21]	2017	Nigeria	CS	100	Stool	Adult	Colonization	P	DDST	56 (56.0)
Jerry et al, 2021 [40]	2017	Nigeria	CS	205	Urine	All age	Infection	P	DDST	23 (11.2)
John-Onwe et al, 2022 [25]	2019	Nigeria	CS	200	Urine	All age	Infection	P	DDST	58 (29.0)
M.R. Rameshkumar et al, 2021 [19]	NR	India	CS	183	Urine, pus, sputum, blood, and vaginal swabs	All age	Infection	P&G	CDT	105 (57.4)
Maharjan et al, 2022 [26]	2019	Nepal	CS	263	Sputum	All age	Infection	P&G	CDT	19 (7.2)
Manyahi et al, 2020 [23]	2017-2018	Tanzania	CS	595	Rectal swabs	Adult	Colonization	P&G	DDST	244 (41.0)
Nwokolo et al, 2022 [27]	NR	Nigeria	CS	363	Urine	All age	Infection	P&G	CDT	44 (12.1)
Osazuwa et al, 2011 [31]	2009-2010	Nigeria	CS	948	Urine & diarrheal stools	All age	Infection	P	DDST	38 (4.0)
Padmavathy et al, 2011 [41]	NR	India	CC	50	Urine	All age	Infection	P	DDST	13 (26.0)
Reinheimer et al, 2017 [42]	2014-2016	Germany	CC	109	Rectal swabs	Adult	Colonization	P	Vitek-2	7 (6.4)
Said et al, 2022 [43]	2021	Tanzania	CS	236	Stool and rectal swabs	Children	Colonization	P&G	CDT	56 (23.7)
Simeneh et al, 2022 [44]	2021	Ethiopia	CS	251	Urine	Adult	Infection	P	DDST	9 (3.6)
Singh et al, 2020 [28]	2017-2018	India	CS	100	Oral swabs	Adult	Colonization	P&G	CDT	14 (14.0)
Subramanya et al, 2019 [30]	2016-2017	Nepal	CS	119	Rectal swabs	All age	Colonization	P&G	DDST	46 (38.7)
Surgers et al, 2022 [24]	2018-2019	France	CS	500	Rectal swabs	Adult	Colonization	P&G	CDT	61 (12.2)
Wilmore et al, 2017 [29]	2014-2015	Zimbabwe	CS	175	Stool	Children	Colonization	P	CDT	24 (13.7)
12 et al, 2022 [45]	2021	Cameroon	CS	175	Vaginal swabs	Adult	Colonization	P&G	DDST	12 (6.9)

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Note: Inv. M

= Investigation methods, Meth

^**

= Method used for phenotypic ESBL confirmation, CS = Cross-sectional, CC = Case‒control, CDT = Combination disk test, DDST = Double‒disc synergy test, NR = Not reported, P = Phenotypic, G = Genotypic, ESBL = Extended-spectrum β-lactamase.

A total of 5305 HIV-positive individuals from 20 studies were included in the meta-analysis of ESBL-producing Enterobacterales. Among 20 studies, only one detected ESBL by using Vitek-2 [42], but others used the combination disk test (CDT) or double disk synergy test (DDST). The minimum and maximum sample sizes were 50 [41] and 948 [31], respectively. A minimum (2.33%) and maximum (57.4%) prevalence of ESBL-producing Enterobacterales were reported by Endalamaw et al. [18] and M.R. Rameshkumar et al. [19], respectively (Table 1).

Pooled prevalence of ESBL-producing Enterobacterales among HIV positive individuals

The overall pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals was 20.30% (931/5305; 95% CI: 15.13–25.47%, P < 0.001), with a high level of heterogeneity (I² = 97.82%, P < 0.001), as presented in (Fig 2).

Moreover, the pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals with infection was 15.77% (318/2850; 95% CI: 10.06–21.49, I² = 97.45%, p < 0.001) (Fig 3), whereas among asymptomatic HIV-positive individuals, it was 23.78% (613/2455; 95% CI: 15.36–32.19, I² = 96.78%, p < 0.001) (Fig 4).

The predominant ESBL-producing pathogens among HIV-positive individuals were K. pneumoniae, with a pooled prevalence of 40.84% (76/217; 95% CI: 26.87–54.81%) (Fig 5), followed closely by E. coli at 40.14% (348/985; 95% CI: 27.83–52.45%) (Fig 6), and Proteus species at 37.2% (24/74; 95% CI: 8.03–66.36%) (SF 4 Fig). In contrast, Citrobacter species were the least commonly identified ESBL producers, with a prevalence of 9.68% (5/55; 95% CI: 1.26–18.10%) (SF 4 Fig). Three studies reported ESBL production in Salmonella spp. The pooled prevalence of ESBL-producing Salmonella spp. was 24.52% (10/42; 95% CI: 7.04–42.00; I² = 94.71%, p ≤ 0.019) (SF 4 Fig).

Regarding infection and colonization with ESBL-producing E. coli and K. pneumoniae among HIV-positive individuals, comparable pooled prevalence rates were observed in both infection and colonization cases. For infection cases, the prevalence of ESBL-producing E. coli was 37.0% (237/537; 95% CI: 20.08–53.94%), while that of K. pneumoniae was 38.76% (42/119; 95% CI: 22.69–54.83%) (SF 4 Fig). Similarly, among colonization cases, the prevalence of ESBL-producing E. coli was 42.93% (343/448; 95% CI: 24.16–61.69%), and that of K. pneumoniae was 42.36% (34/98; 95% CI: 15.97–68.74%) (SF 4 Fig).

Publication bias

Publication bias was assessed to determine bias related to published and unpublished studies. The analysis produced an asymmetric funnel plot, which indicated the presence of publication bias (Fig 7). Moreover, Egger’s test revealed a significant publication bias (P < 0.001)(SF 3 Table).

Nonparametric trim-and-fill analysis of the pooled prevalence of ESBL-producing Enterobacterales

A nonparametric trim-and-fill analysis was conducted to address the observed publication bias. After imputing data on the left, the pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals across the globe remained stable at 20.30% (95% CI: 15.13–25.47%) (SF 3 Table). Conversely, when analyzing 21 studies with one data points imputed on the right, the pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals was slightly higher at 21.58% (95% CI: 14.34–28.82%) (SF 3 Table).

Sensitivity analysis

A sensitivity analysis was performed via a random effects model to assess the impact of individual studies on the combined estimate. The pooled prevalence of ESBL-producing pathogens that was obtained after individual studies were excluded was within the 95% CI of the total combined estimate. This shows that no single study had an effect on the overall pooled prevalence (SF 3 Fig and Table).

Subgroup analysis

To address heterogeneity, subgroup analysis was carried out by geographical location, publication year, age group, and phenotypic ESBL confirmation methods. When subgroup analysis was performed by continent, the highest pooled prevalence of ESBL-producing pathogens among HIV patients was observed in Asia, at 28.55% (195/715; 95% CI: 8.41–48.70, I² = 97.85%, P < 0.001), followed by Africa, at 19.12% (666/3981; 95% CI: 12.98–25.25, I² = 98.07%, P < 0.001). On the other hand, the lowest pooled prevalence was found in Europe, at 9.60% (68/609; 95% CI: 3.97–15.24, I² = 77.07%, P = 0.04) (Fig 8).

Similarly, subgroup analysis on the basis of the publication year of studies revealed that the highest pooled estimate was 21.53% (803/3904; 95% CI: 14.66–28.39, I² = 98.12%, P < 0.001) in and after 2020, whereas for studies published before 2020, the prevalence was 16.72% (128/1401; 95% CI: 7.17–26.27, I² = 95.10%, P = 0.001) (Fig 9).

In addition, a subgroup analysis was conducted based on patient age groups. The pooled prevalence of ESBL-producing Enterobacterales did not show a substantial difference across age categories. The prevalence was reported as 19.03% (416/2903; 95% CI: 12.99–25.07, I² = 71.87%, P = 0.03) in children, 19.57% (112/572; 95% CI: 8.39–30.75, I² = 98.29%, P < 0.001) in adults, and 21.25% (403/1830; 95% CI: 14.43–28.07, I² = 97.88%, P < 0.001) in studies involving all age groups (Fig 10).

Furthermore, a subgroup analysis was conducted based on the type of investigation method. The highest pooled prevalence of ESBL-producing pathogens among HIV-positive patients was reported in studies employing genotypic methods (24.33%, 657/2653; 95% CI: 15.02–33.65; I² = 97.69%; P < 0.001), followed by studies using phenotypic methods (15.42%, 274/2652; 95% CI: 10.53–20.31; I² = 96.11%; P < 0.001) (Fig 11).

We also performed subgroup analysis in terms of phenotypic ESBL detection methods. The highest pooled prevalence was observed using the double-disk synergy test (DDST), at 22.09% (569/3215; 95% CI: 14.80–29.37, I² = 98.38%, P < 0.001), followed by the combined disk test (CDT), at 19.70% (355/1981; 95% CI: 11.91–27.50, I² = 96.04%, P < 0.001). The lowest pooled prevalence was recorded using the Vitek-2 method, at 6.42% (7/109; 95% CI: 1.82–11.02, I² = 0.0%, P < 0.001) (SF 5 Fig).

Risk factors for the prevalence of ESBL producers among HIV-positive individuals

A meta-analysis could not be performed because of the small number of studies reporting risk factors. Among the 20 included studies, only 4 reported risk factors; among these, variability in variables such as a history of antibiotic use, hospital admission, and low cluster of differentiation 4 (CD4) T lymphocyte counts was a risk factor for a higher prevalence of ESBL-producing Enterobacterales among HIV-positive individuals (Table 2).

Table 2. Significant risk factors in some of the included studies.

Study	Risk factors assessed	Analysis	Significant risk factors	Odds ratio (95% CI)
Subramanya et al, 2019 [30]	Age, sex, occupation, CD4 count, ART, ART duration, admitted to hospital in at 6 m, history of antibiotic use in at 6 m, animal contact (domestic and livestock), using medication over-the-counter, international travel, food habit	Multivariate	With ART	1.537 (0.349,6.762)
			Admitted to hospital in the previous 6 m	3.638 (0.793,16.68)
			Close contact with livestock	1.153 (0.515,2.581)
			Using medication over-the-counter	1.988 (0.898,4.401)
Bayleyegn et al, 2021 [39]	Age, sex, residence, educational status, opportunistic infections, presence of fever, WHO stage of HIV, ART type, ART duration, history of antibiotic use, viral load, presence of diarrhea, eating uncooked products, eating row vegetable	Multivariate	History of antibiotic use	3.2 (1.05–9.9)
Manyahi et al, 2020 [23]	Age, sex, residence, educational status, WHO stage of HIV, CD4 count, admitted to hospital in at 12 m, history of antibiotic use in at 1 m	Multivariate	CD4 count <350	1.78 1.03–3.09
Manyahi et al, 2020 [23]		Multivariate	History of antibiotic use in the previous 1 m	1.55 1.08–2.22
Wilmore et al, 2017 [29]	Age, gender, CD4, viral load, ART duration, admitted to hospital with pneumonia in last 12 m, admitted to hospital in at 12 m	Multivariate	With ART ≤ 1year	8.47 (2.22–2.27)
Wilmore et al, 2017 [29]		Multivariate	Admitted to hospital with pneumonia in last 12 m	8.47 (1.12–64.07)

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Note: ART = antiretroviral therapy, HIV = human immunodeficiency virus, WHO = World Health Organization, CL = confidence interval, M = month, CD4 = cluster of differentiation 4.

Types of ESBL enzyme-encoding genes via Enterobacterales among HIV-positive individuals

Although the included studies employed heterogeneous genotyping techniques, bla_CTX-M (73/150, 48.7%) was the most prevalent genotype, followed by bla_TEM (49/150, 32.7%) among the commonly reported ESBL enzyme-encoding genes, as documented in five studies (Table 3).

Table 3. Types of genes in some studies that carry out genotypic analysis.

Study (Author, Year)	No of isolates subjected to genotype test	Types of isolates			Types of genes
Study (Author, Year)	No of isolates subjected to genotype test	Types of isolates	Total ESBL gene	bla _SHV	bla _TEM	bla _CTX-M	bla _CTX-M + bla _TEM
Nwokolo et al, 2022 [27]	44	E. coli	26	7 (26.9)	8 (30.8)	11 (42.3)
Maharjan et al, 2022 [26]	12	E. coli	9	–	2 (22.2)	3 (33.3)	4 (44.5)
	17	K.pneumoniae	7	–	0	3 (42.9)	4 (57.1)
12 et al, 2022 [45]	14	E. coli	12	–	6 (50.0)	1 (8.3)	5 (41.7)
	5	K. pneumoniae	4	–	–	4 (100)	–
Dimani et al, 2023 [20]	45	E. coli	63	3 (4.7)	27 (42.9)	33 (52.4)	–
	11	K. pneumoniae	12	4 (33.3)	3 (25.0)	5 (41.7)	–
Singh et al, 2020 [28]	10	E. coli	9	0	2 (22.2)	7 (77.8)	–
	17	K. pneumoniae	8	1 (12.5)	1 (12.5)	6 (75.0)	–
Total	175	–	150	15 (10.0)	49 (32.7)	73 (48.7)	13 (8.6)

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Note: ESBL = extended-spectrum β-lactamase, bla_TEM = Temoneira β-lactamase, bla_SHV = sulfhydryl reagent variable β-lactamase, bla_CTX-M = cefotaxim-hydrolizing β-lactamase..

Discussion

The management of antibiotic-resistant bacterial infections especially those caused by Enterobacterales poses a significant challenge in the context of infectious diseases like HIV [46]. Although not all ESBL-producing strains meet the strict definition of multidrug resistance (MDR), the production of ESBLs often confers resistance to multiple β-lactam antibiotics and is frequently associated with co-resistance to other antimicrobial classes. These pathogens are commonly linked to nosocomial infections [14]. In this context, our systematic review and meta-analysis aimed to estimate the global burden of ESBL-producing Enterobacterales among individuals living with HIV.

In our systematic review and meta-analysis, the overall pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals was 20.30% (95% CI: 15.13–25.47%, P < 0.001), with a high level of heterogeneity (I² = 97.82%, p < 0.001). This significant prevalence of ESBLs among these populations may be due to the increased number of antibiotics consumed and increased risk of acquisition of resistant pathogens during healthcare visits and hospitalizations [47]. These populations are immunocompromised and need more frequent healthcare appointments and are vulnerable to comorbid conditions, which require hospital admissions, than are the general population [48].

The highest pooled prevalence of ESBL-producing pathogens among HIV-positive individuals was reported to be colonization 23.78% (95% CI: 15.36–32.19, I² = 96.78%, p < 0.001), followed by infection 15.77% (95% CI: 10.06–21.49, I² = 97.45%, p < 0.001). The higher prevalence may be explained by the methods used to report on colonization, sample size, method of detection, culture media. This may be because the gut microbiota is mostly composed of Enterobacterales, and HIV infection alters the composition of the microbiome and decreases the number of CD4 + T cells in the gut-associated lymphoid tissue, which is associated with microbiota dysbiosis that favors colonization and subsequent infections with resistant strains [49,50].

In the present meta-analysis, the predominant ESBL-producing pathogens among HIV-infected patients were K. pneumoniae, with a pooled prevalence of 40.84% (95% CI: 26.87–54.81%), followed closely by E. coli at 40.14% (95% CI: 27.83–52.45%). These organisms are known to resist beta-lactam antibiotics through the production of ESBL enzymes [51,52]. K. pneumoniae is most commonly associated with healthcare-associated infections, whereas E. coli is typically linked to community-acquired infections. As a result, infections caused by these pathogens may contribute to increased complications in HIV-infected patients [53].

In this meta-analysis, a high level of heterogeneity (I² = 97.82%) was observed. This is not surprising given the differences in study settings, patient statuses, age groups, sample types, publication years and methods used for the detection of ESBLs. To determine the possible sources of heterogeneity, subgroup analysis was performed by continent, and the highest pooled prevalence of ESBL-producing pathogens among HIV-positive individuals was reported in Asia: 28.55% (95% CI: 8.41–48.70, I² = 97.85%, P < 0.001), followed by the African continent 19.12% (95% CI: 12.98–25.25, I² = 98.07%, P < 0.001). However, the lowest pooled prevalence was found in Europe, at 9.60% (95% CI: 3.97–15.24, I² = 77.07%, P = 0.04). This is because the use of trimethoprim‒sulfamethoxazole prophylaxis in developed nations is decreasing because of the early diagnosis of HIV and well-controlled antiretroviral therapy (ART), which reduces immunosuppression and bacterial infections [54].

However, the high burden of HIV infection and weak health systems to diagnose HIV early, inadequate adherence and poorly controlled ART make the immune system weakened and susceptible to bacterial infections in low-income countries. Additionally, as opportunistic infections are common among HIV-positive individuals in these countries, trimethoprim‒sulfamethoxazole prophylaxis is widely used [55]. For this reason, this antibiotic can be used to coselect resistant strains among these populations [9]. Several studies have reported that trimethoprim-sulfamethoxazole prophylaxis is mostly associated with increased non-susceptibility of Enterobacterales to beta-lactam antibiotics and an increased risk of ESBL-producing Enterobacterales [9,56,57].

Another suggested reason for the highest prevalence of ESBL-producing pathogens among HIV-positive individuals in Asia and Africa is the poor antibiotic stewardship program and low control mechanism for antibiotic usage, which causes overuse and misuse of antibiotics in healthcare facilities that facilitate resistant infections [58]. Additionally, poor infection prevention mechanisms, such as poor hygiene and sanitation practices, environmental contamination and inadequate decontamination of medical devices, aggravate colonization and infection with resistant pathogens among HIV-positive individuals in developing countries [58,59].

According to the subgroup analysis by publication year, the highest pooled estimate of 21.53% (95% CI: 14.66–28.39, I² = 98.12%, P < 0.001) was observed in studies published in and after 2020, whereas before 2020, the prevalence was 16.72% (95% CI: 7.17–26.27, I² = 95.10%, P = 0.001). This gap may be due to the emergence of multidrug-resistant bacteria because the prevalence of ESBL-producing bacteria has increased over time, and recently studied papers may include a high number of ESBL-producing pathogens [60].

Furthermore, the subgroup analysis was carried out based on the investigation methods. Accordingly, the highest pooled prevalence of ESBL-producing pathogens among HIV patients was reported in studies that included genotypic investigations (24.33%, 95% CI: 15.02–33.65, I² = 97.69%, P < 0.001), followed by phenotypic investigations (15.42%, 95% CI: 10.53–20.31, I² = 96.11%, P < 0.001). The higher pooled prevalence of ESBL-producing pathogens reported in studies using genotypic methods may be attributed to the greater sensitivity and specificity of these techniques in detecting resistance genes, including those that are silent or weakly expressed. In contrast, phenotypic methods may underestimate prevalence due to their reliance on observable resistance, which can be affected by gene expression levels or overlapping resistance mechanisms. Additionally, genotypic studies may have been conducted in settings with higher antibiotic pressure or more advanced diagnostic capacity, contributing to the observed differences [61].

In our systematic review, among the 20 included studies, only 2 reported that a history of antibiotic use in the previous month was a risk factor for infection and/or colonization with ESBL-producing pathogens among HIV-positive individuals. Additionally, the highest prevalence of ESBL-producing pathogens was reported in HIV-positive individuals who were admitted to the hospital for the last 6 and 12 months. Several previous studies identified prior hospitalization and antibiotic exposure as risk factors for antibiotic-resistant infections [12,47,62]. Patients may acquire resistant pathogens from hospitals, which may be due to selective pressure; when patients use antibiotics, sensitive bacterial strains are eliminated, leaving behind or selecting those variants that can resist them [47]. As cephalosporins are the most commonly used antibiotics for the treatment of various infections, they favor ESBL-producing strains [63].

Additionally, some studies have shown that taking ART for less than one year is a risk factor for ESBL incidence, and the risk of infection with ESBL-producing pathogens among HIV-positive individuals varies according to the CD4 count and is greatest in HIV-positive individuals with CD4 counts <350 cells/mm³. Low immunity with low CD4 + T cells is associated with an increased risk of opportunistic infections, increasing the likelihood of antimicrobial use and hospitalization. Consequently, this phenomenon predisposes resistant pathogens to the emergence of ESBL-producing strains [64].Among the various ESBL enzyme-encoding genes, bla_CTX-M is the most prevalent (48.7%), followed by bla_TEM (32.7%). The dominance of bla_CTX-M genes is largely attributed to their efficient dissemination through mobile genetic elements such as plasmids, transposons, insertion sequences, and integrons, which facilitate the horizontal transfer of resistance genes among Enterobacterales and other gram-negative bacilli in clinical settings worldwide [65]. In developing countries, where infection prevention and control measures are often limited, this gene transfer is even more widespread occurring not only in humans but also in animals and the environment [66]. Because these mobile genetic elements frequently carry multiple resistance determinants, pathogens harboring ESBL genes are also more likely to acquire additional MDR traits [65,66]. As a result, infections caused by these organisms are harder to treat. Therefore, infection with these pathogens complicates treatment options and intensifies the level of care required for immunocompromised patients, such as those living with HIV.

Limitations

Study restriction by language and year of publication are the main limitations of this study. Furthermore, few countries are overrepresented, as the majority of studies are from Africa, specifically, sub-Saharan Africa; however, owing to the high burden of HIV in this region, accurate generalization is difficult. Since a few studies reported the risk factors and the heterogeneous variables used, a meta-analysis was not performed on the associated factors.

Conclusion and recommendations

This study revealed a significant prevalence of ESBL-producing Enterobacterales among HIV-positive individuals, with K. pneumonia and E. coli being the dominant ESBL producers. The highest magnitude of ESBL-producing pathogens was observed in Asia and Africa. With respect to the types of ESBL enzyme-encoding genes, the most prevalent was bla_CTX-M followed by bla_TEM. Equitable allocation of resources across all regions is needed to reduce mortality due to complications in HIV patients with severe bacterial infections; the regions with the highest prevalence rates should pay attention to early diagnosis of HIV, adequate adherence and well-controlled ART. Consequently, this helps to reduce immunosuppression and bacterial infections. Early identification of infections and colonization with antibiotic-resistant pathogens among HIV patients is also needed.

Supporting information files

SF 1. Table, PRISMA checklist.

(DOCX)

pone.0321873.s001.docx^{(22.7KB, docx)}

SF 2. Table, quality assessment of the studies included in a systematic review and meta-analysis.

(DOCX)

pone.0321873.s002.docx^{(35.4KB, docx)}

SF 3. Doc, Publication bias and Sensitivity analysis.

(DOCX)

pone.0321873.s003.docx^{(227.6KB, docx)}

SF 4. Figs, forest plots showed the pooled prevalence of ESBL by each bacterial species.

(DOCX)

pone.0321873.s004.docx^{(104.8KB, docx)}

SF 5. Doc, Subgroup analysis.

(DOCX)

pone.0321873.s005.docx^{(138KB, docx)}

SF 6. Table for all studies identified in the literature search.

(DOCX)

pone.0321873.s006.docx^{(678.7KB, docx)}

List of abbreviations

AMR: Antimicrobial resistance
ART: Antiretroviral therapy
CDT: Combination disk test
DDST: Double-disk synergy test
ESBL: Extended-spectrum β-lactamase
HIV: Human immunodeficiency virus
MDR: Multidrug resistance
WHO: World Health Organization.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. 2025 Jun 10;20(6):e0321873. doi: 10.1371/journal.pone.0321873.r001

Author response to Decision Letter 0

14 Sep 2024

PLoS One. doi: 10.1371/journal.pone.0321873.r002

Decision Letter 0

Amir Nutman

30 Mar 2025

Dear Dr. Tigabie,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 14 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Amir Nutman

Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors,

Thank you for submitting your manuscript, “Extended-spectrum β-lactamase-producing gram-negative bacilli among people living with human immunodeficiency virus across the globe: a systematic review and meta-analysis” to PLOS ONE. Based on the reviewers’ comments, I invite you to submit a revised version.

Please address all reviewer points in a point-by-point response and highlight changes in the manuscript. This decision does not guarantee acceptance, but I believe the work has potential pending revision.

I look forward to your resubmission.

Best regards,

Amir

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: The authors conducted a systematic review and meta-analysis on the prevalence of ESBL in Gram negative bacteria among people with HIV. While the methods used for the analysis are appropriate, I have several concerns with regards to how the data are interpreted and reported.

Firstly, the main results on the prevalence of ESBL should be reported according to bacterial species and type (colonisation vs. infection). It is known that there are differences in ESBL prevalence between common Gram negatives such as E. coli and K. pneumoniae and pooling results across organisms is less meaningful. Further the authors should present as a main analysis (instead of a subgroup) the prevalence of ESBL in colonisation and infection samples.

Secondly the authors should note that for A. baumanii and P. aeruginosa, there are other mechanisms that play a more important role in beta-lactam resistance than ESBL-production. For this reason, the authors should restrict the focus of the manuscript on Enterobacterales and exclude A baumanii and P. aeruginosa.

Lastly, the authors should revise the manuscript to improve clarity and avoid repetitions. More specific comments are added below.

Lines 62-69: use concordant referencing. Currently you are reporting on data from various sources and the figures are somewhat conflicting. The O’Neill report which is almost 10 years old may have overestimated the number of deaths due to AMR. The paragraph would be easier to read if only one set of figures per point made would be used. Also in line 66 the sentence moves from economic losses in the US to global economic losses which is confusing.

Line 72: “Furthermore, the surge of infections that cause immune suppression, such as human immunodeficiency virus “ consider rephrasing as the infection you are referring to is HIV and there is no surge of multiple infections associated with immunosuppression. (unless you mean conditions associated with immunosuppression e.g. long-term steroids etc.

Lines 82-84: introduce the epidemiology of HIV before introducing how it relates to resistance development

Line 90: “Among bacterial pathogens, gram negative bacilli are the most dangerous …” while it is true that gram-negative organisms pose more problems because of their resistance to antibiotics, they are not necessarily more dangerous (unless a reference is provided to support that statement e.g. that bacterial infections due to gram-negatives cause more deaths).

Line 95: “cephalosporins, and aztreonam, which are easily available” remove aztreonam from the listing as it is not easily available and commonly used

Line 97: “Enterobacteriaceae, Pseudomonas aeruginosa (P. aeruginosa), and Acinetobacter baumannii (A. baumannii) are the predominant gram-negative bacilli that produce ESBL enzymes “ please revise the sentence – the main mechanisms associated with resistance for P aeruginosa and A. baumanii are not ESBL-production.

Lines 105-107 – “the number of ESBL-producing gram-negative bacilli among HIV-positive individuals varies from 2.3% to 65.6%” – these are proportions not numbers

Lines 109-110: “On the one hand, various studies in the past reported higher ESBLs among HIV-positive individuals [20-29]. On the other hand, some studies reported that ESBL producers were more common among HIV-negative patients than among HIV-positive individuals [30-32].” – please consolidate these sentences to avoid repetitions

Line 139: please clarify in the methods whether the review included studies reporting exclusively on people living with HIV or it also included studies with mixed populations which reported on AMR prevalence by HIV status

Line 157: “The three reviewers listed above, MT, KT, and AB, were independently assessed to assess the quality of the included studies.” Please revise to avoid repetition

Figure 1: conventionally in the PRISMA diagram, the studies are reported separately as to how many were excluded in the title and abstract screening (reason for exclusion not necessary) and how many were excluded in the full text phase (with reason for exclusion).

Line 214 and above: be specific in the methods on how the prevalence was calculated for case-control studies (depending on the study design, might only be possible to calculate prevalence in the cases)

Table 1: please check and/or comment on including studies on infection which reported on stool samples. In this setting ESBL-producing organisms are also likely to represent colonisation (e.g. the study by Falodun reference #23 et al is clearly reporting on colonisation). Also check as there is an error with reference #22 which is a different study by Falodun et al. (not Israel)

Line 231: please note that it is not appropriate to pool prevalence across very different bacterial species and sample types. At least the pooling should be done separately for colonisation and infection and ideally separate for the main Enterobacterales species. This should not be treated as a subgroup analysis but rather the main analysis. I would suggest that you omit Pseudomonas and Acinetobacter completely from the analysis and manuscript as these organisms have additional mechanisms causing beta-lactam resistance, other than ESBL.

Table 2: “Rate of ESBL…” heading – please rename as this is not a rate (prevalence).

Table 2: Comment separately in the manuscript text on the prevalence of ESBL in Salmonella – 20% is quite high and concerning for clinical practice.

Table 3: can be omitted

Figure 3 should be redrawn as it is difficult to read with a black background. Also the numbers on the x-axis are overlapping. The figure can be included in the supplement.

Line 279: the subgroup analysis on method used can be omitted (or included in the supplement). For the other subgroup analyses please see my comment above. The authors could also add a subgroup analysis by organism and type (colonisation vs. infection) for community-acquired and hospital associated infections

Table 5 and Supplement: the genes should be reported according to the bacterial species in which they were identified (consider reporting for E. coli and K. pneumoniae only). Please also specify which SHV/CTX-M/TEM/OXA genes were reported as not all of them are ESBL

Line 322: please rephrase. The organisms are not multidrug resistant because they are ESBL-producers (there is a somewhat old definition of MDR and being ESBL does not suffice).

Line 339: please revise as E. coli is a common cause of community-acquired infections

Line 377: the higher prevalence may be explained by the methods used to report on colonisation (denominators, method of detection – culture media).

Lines 401-410: paragraph has repetitive sentences please revise

Reviewer #2: This systematic review and meta-analysis provide valuable insights into ESBL prevalence among HIV-positive individuals. While the study is methodologically strong, improvements in data selection, bias reduction, and clinical interpretation could enhance its impact. Future research should focus on treatment outcomes, stewardship interventions, and emerging resistance mechanisms to inform better infection control policies in HIV care settings.The study adheres to PRISMA guidelines, ensuring methodological transparency. It addresses a critical intersection of HIV and antimicrobial resistance (AMR), a growing concern for global health.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes: Rahul Garg

**********

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PLoS One. 2025 Jun 10;20(6):e0321873. doi: 10.1371/journal.pone.0321873.r003

Author response to Decision Letter 1

17 Apr 2025

PONE-D-24-40800

Extended-spectrum β-lactamase-producing gram-negative bacilli among people living with human immunodeficiency virus across the globe: a systematic review and meta-analysis

PLOS ONE

Dear Dr. Tigabie,

Please submit your revised manuscript by May 14 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Amir Nutman

Academic Editor

PLOS ONE

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Authors: We appreciate for spending your precious time and forwarding your valuable comments, which have significantly improved our manuscript. We are also grateful for this positive feedback. Please see below, bold, for a point-by-point response to the reviewers. We've copied your comments and responses below to make things easier for you. All line numbers refer to the revised manuscript file.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Authors: we have prepared the manuscript based on PLOS ONE's style requirements.

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- The points extracted from images for analysis.

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Authors: we all authors decide and agreed on PLOS ONE's data sharing plan. All authors decide and agreed data availability statement.

Authors: we provided ethics statement in the Methods section of the manuscript.

Authors: we provided captions for the Supporting Information files at the end of the manuscript

6. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

A numbered table of all studies identified in the literature search, including those that were excluded from the analyses.

For every excluded study, the table should list the reason(s) for exclusion.

If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study:

Name of data extractors and date of data extraction

Confirmation that the study was eligible to be included in the review.

All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.

An explanation of how missing data were handled.

Authors: we provided a table that included all studies identified in the literature search, along with reason(s) for exclusion for every excluded study. We uploaded this table in the Supporting Information files.

We also, provided a table showing the completed risk of bias as well as Name of data extractors and date of data extraction for included studies.

Additional Editor Comments:

Dear Authors,

I look forward to your resubmission.

Best regards,

Amir

[Note: HTML markup is below. Please do not edit.]

Response to Academic Editor

Authors: Thank you for your positive feedback; we appreciate your feedback. We have revised the entire manuscript as necessary and have attempted to address the comments from the reviewers.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Response to Reviewers

Authors: we would like to say thank you for reviewing our work and making insightful suggestions and comments that helped to strengthen our manuscript. We have revised the manuscript as necessary.

Authors: Thank you for your positive feedback.

Reviewer #1: Firstly, the main results on the prevalence of ESBL should be reported according to bacterial species and type (colonisation vs. infection). It is known that there are differences in ESBL prevalence between common Gram negatives such as E. coli and K. pneumoniae and pooling results across organisms is less meaningful. Further the authors should present as a main analysis (instead of a subgroup) the prevalence of ESBL in colonisation and infection samples.

Authors: Thank you for bringing this issue to our intention. We have revised the analysis according to bacterial species and type (colonisation vs. infection). (Please refer to the revised manuscript's result section line # 248-272 and Supplementary File 4, Fig).

Reviewer #1: Secondly the authors should note that for A. baumanii and P. aeruginosa, there are other mechanisms that play a more important role in beta-lactam resistance than ESBL-production. For this reason, the authors should restrict the focus of the manuscript on Enterobacterales and exclude A baumanii and P. aeruginosa.

Authors: Thank you for your positive feedback. We have reanalyzed the data after excluding A baumanii and P. aeruginosa, now the manuscript focused on only about Enterobacterales (Please refer to the revised manuscript).

Reviewer #1: Lastly, the authors should revise the manuscript to improve clarity and avoid repetitions. More specific comments are added below.

Authors: Thank you for your input. We have accepted your comment and we tried to amend to improve clarity and avoid repetitions (Please refer to the revised manuscript).

Reviewer #1: Lines 62-69: use concordant referencing. Currently you are reporting on data from various sources and the figures are somewhat conflicting. The O’Neill report which is almost 10 years old may have overestimated the number of deaths due to AMR. The paragraph would be easier to read if only one set of figures per point made would be used. Also in line 66 the sentence moves from economic losses in the US to global economic losses which is confusing.

Authors: Thank you for raising this interesting point. We have changed the whole paragraph with updated data. (Please refer to the revised manuscript line # 65-72).

Reviewer #1: Line 72: “Furthermore, the surge of infections that cause immune suppression, such as human immunodeficiency virus “consider rephrasing as the infection you are referring to is HIV and there is no surge of multiple infections associated with immunosuppression. (unless you mean conditions associated with immunosuppression e.g. long-term steroids etc.

Authors: We appreciate your feedback. We have rephrased and corrected a typing error (Please refer to the revised manuscript line # 75-79).

Reviewer #1: Lines 82-84: introduce the epidemiology of HIV before introducing how it relates to resistance development

Authors: Thank you for raising this interesting point. We incorporated th

Attachment

Submitted filename: Response to Reviewers.docx

pone.0321873.s008.docx^{(37.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0321873.r004

Decision Letter 1

Amir Nutman

27 Apr 2025

Dear Dr. Tigabie,

Please submit your revised manuscript by Jun 11 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Amir Nutman

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Thank you for your submission.

After reviewing the revised manuscript, I find it acceptable pending minor revisions:

1. The manuscript would benefit from language editing by a fluent English speaker to improve overall readability.

2. When reporting prevalence percentages, please also indicate the numerator and denominator (e.g., x/y, z%) to enhance clarity.

3. In Supplementary Table 2, only one author is listed as performing data extraction, which does not align with the description in lines 212–213 of the main text. Please correct this inconsistency.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

**********

Reviewer #1: All my previous comments have been addressed.

However I am slightly confused by the different prevalences reported - perhaps because of numerators and denominators "The predominant ESBL producers were K. pneumoniae, with a pooled prevalence of 40.84% (95% CI: 26.87–54.81%), followed closely by E. coli at 40.14% (95% CI: 27.83–52.45%). In the subgroup analysis, the highest magnitude of ESBL producing pathogens was observed in Asia (28.5534.97%), followed by Africa (19.1220.75%). Additionally, the highest pooled prevalence of ESBL-producing pathogens among HIV-positive individuals was reported to be colonization 23.78% (95% CI: 15.36–32.19, I² = 96.78%, p <0.001), followed by infection 15.77% (95% CI: 10.06–21.49, I² = 97.45%, p < 0.001). "

The pooled prevalence of ESBL E coli is reported above at 40% and below at 15-23%. Also for the subgroup analyses by country there are prevalences around 20% by continent while overall it is 40%.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

**********

PLoS One. 2025 Jun 10;20(6):e0321873. doi: 10.1371/journal.pone.0321873.r005

Author response to Decision Letter 2

6 May 2025

Response to Academic Editor and Reviewers

Authors: We appreciate for spending your precious time and forwarding your valuable comments, which have significantly improved our manuscript. We are also grateful for this positive feedback. Please see below, bold, for a point-by-point response to Academic Editor and the reviewers. We've copied your comments and responses below to make things easier for you.

Academic Editor

1. The manuscript would benefit from language editing by a fluent English speaker to improve overall readability.

Authors: Thank you for your positive feedback. We have revised the entire manuscript with the assistance of a local editor and a professor to ensure appropriate language editing

2. When reporting prevalence percentages, please also indicate the numerator and denominator (e.g., x/y, z%) to enhance clarity.

Authors: Thank you for bringing this issue to our intention. We have provided the numerator and denominator of the prevalence result along with percentages to enhance clarity. Please do not be confused by the fact that the pooled prevalence is not identical to the crude proportion calculated. For example, the pooled prevalence of 20.30% is not identical to the crude proportion calculated as 931/5305. In meta-analysis, the pooled prevalence (20.30%) generated by STATA is not a simple average or direct proportion. Rather, it is weighted summary estimates derived from a meta-analysis model specifically, a random-effects model which accounts for variation across studies, differential weighting, and heterogeneity. Therefore, we kindly request that the prevalence results to be interpreted within this context.

3. In Supplementary Table 2, only one author is listed as performing data extraction, which does not align with the description in lines 212–213 of the main text. Please correct this inconsistency.

Authors: Thank you for bringing this to our attention. We have reviewed and corrected the inconsistency in the number of authors between Supplementary Table 2 and the main text.

Reviewer #1: All my previous comments have been addressed.

Authors: We appreciate your feedback. We have checked and updated prevalence results via provided the numerator and denominator of the prevalence result along with percentages to enhance clarity. However, Please do not be confused by the fact that the pooled prevalence is not identical to the crude proportion calculated. For example, the pooled prevalence of 20.30% is not identical to the crude proportion calculated as 931/5305. In meta-analysis, the pooled prevalence (20.30%) generated by STATA is not a simple average or direct proportion. Rather, it is weighted summary estimates derived from a meta-analysis model specifically, a random-effects model which accounts for variation across studies, differential weighting, and heterogeneity. Therefore, we kindly request that the prevalence results to be interpreted within this context.

Reviewer #1: The pooled prevalence of ESBL E coli is reported above at 40% and below at 15-23%. Also for the subgroup analyses by country there are prevalences around 20% by continent while overall it is 40%.

Authors: Thank you for reflecting on your concern. The overall pooled prevalence of ESBL-producing E. coli (e.g., 40%) represents a weighted average from all included studies, regardless of location, time, or population. Subgroup analyses by continent show averages within smaller groups, often with different numbers of studies, sample sizes, and local epidemiology. It's entirely possible for subgroups to show lower prevalence rates like 15–23% while the overall prevalence is higher, especially when High-prevalence studies (e.g., from specific countries) had large sample sizes or more weight in the analysis. Furthermore, there are fewer studies from low-prevalence areas, giving them less impact on the pooled estimate.

Attachment

Submitted filename: Response_to_Reviewers_auresp_2.docx

pone.0321873.s009.docx^{(18.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0321873.r006

Decision Letter 2

Amir Nutman

19 May 2025

<p>Extended-spectrum β-lactamase-producing Enterobacterales among people living with human immunodeficiency virus across the globe: a systematic review and meta-analysis

PONE-D-24-40800R2

Dear Dr. Tigabie,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

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Reviewer #1: The authors have provided responses to my comments (from the previous round of review) and I have no further comments.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

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PLoS One. doi: 10.1371/journal.pone.0321873.r007

Acceptance letter

Amir Nutman

PONE-D-24-40800R2

PLOS ONE

Dear Dr. Tigabie,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SF 1. Table, PRISMA checklist.

(DOCX)

pone.0321873.s001.docx^{(22.7KB, docx)}

SF 2. Table, quality assessment of the studies included in a systematic review and meta-analysis.

(DOCX)

pone.0321873.s002.docx^{(35.4KB, docx)}

SF 3. Doc, Publication bias and Sensitivity analysis.

(DOCX)

pone.0321873.s003.docx^{(227.6KB, docx)}

SF 4. Figs, forest plots showed the pooled prevalence of ESBL by each bacterial species.

(DOCX)

pone.0321873.s004.docx^{(104.8KB, docx)}

SF 5. Doc, Subgroup analysis.

(DOCX)

pone.0321873.s005.docx^{(138KB, docx)}

SF 6. Table for all studies identified in the literature search.

(DOCX)

pone.0321873.s006.docx^{(678.7KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0321873.s008.docx^{(37.2KB, docx)}

Attachment

Submitted filename: Response_to_Reviewers_auresp_2.docx

pone.0321873.s009.docx^{(18.6KB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Extended-spectrum β-lactamase-producing Enterobacterales among people living with human immunodeficiency virus across the globe: A systematic review and meta-analysis

Mitkie Tigabie

Abebe Birhanu

Muluneh Assefa

Getu Girmay

Kebebe Tadesse

Roles

Abstract

Background

Methods

Results

Conclusion and recommendations

Introduction

Methods

Study design and protocol registration

Search strategy

Outcome of interest

Eligibility criteria

Quality assessment

Data extraction

Statistical analysis

Results

Study selection and identification

Fig 1. A flow diagram of study selection for systematic review and meta-analysis of ESBL-producing Enterobacterales among HIV-positive individuals.

Summary of the risk of bias results

Characteristics of the studies included in the systematic review and meta-analysis

Table 1. Characteristics of individual studies included in the meta-analysis of ESBL-producing Enterobacterales among HIV-positive individuals across the globe, 2024.

Pooled prevalence of ESBL-producing Enterobacterales among HIV positive individuals

Fig 2. Forest plot showing overall pooled prevalence of ESBL-producing Enterobacterales among HIV-positive individuals.

Fig 3. Forest plot for the pooled prevalence of ESBL-producing Enterobacterales among infection case.

Fig 4. Forest plot for the pooled prevalence of ESBL-producing Enterobacterales among colonization case.

Fig 5. Forest plot showing the pooled prevalence of ESBL-producing K. pneumoniae among HIV-positive individuals.

Fig 6. Forest plot showing the pooled prevalence of ESBL-producing E. coli among HIV-positive individuals.

Publication bias

Fig 7. Funnel plot showing publication bias for ESBL-producing Enterobacterales among HIV-positive individuals.

Nonparametric trim-and-fill analysis of the pooled prevalence of ESBL-producing Enterobacterales

Sensitivity analysis

Subgroup analysis

Fig 8. Subgroup analysis of ESBL-producing Enterobacterales among HIV-positive individuals by continent.

Fig 9. Subgroup analysis of ESBL-producing Enterobacterales by year of publication.

Fig 10. Forest plot showing subgroup analysis of ESBL-producing Enterobacterales via age categories.

Fig 11. Forest plot showing subgroup analysis of ESBL-producing Enterobacterales via investigation methods.

Risk factors for the prevalence of ESBL producers among HIV-positive individuals

Table 2. Significant risk factors in some of the included studies.

Types of ESBL enzyme-encoding genes via Enterobacterales among HIV-positive individuals

Table 3. Types of genes in some studies that carry out genotypic analysis.

Discussion

Limitations

Conclusion and recommendations

Supporting information files

List of abbreviations

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Decision Letter 0

Amir Nutman

Roles

Author response to Decision Letter 1

Decision Letter 1

Amir Nutman

Roles

Author response to Decision Letter 2

Decision Letter 2

Amir Nutman

Roles

Acceptance letter

Amir Nutman

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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