Burden of mortality and its predictors among TB-HIV co-infected patients in Ethiopia: Systematic review and meta-analysis

Amare Kassaw; Demewoz Kefale; Tigabu Munye Aytenew; Molla Azmeraw; Muluken Chanie Agimas; Shegaw Zeleke; Mastewal Ayehu Sinshaw; Nigatu Dessalegn; Worku Necho Asferie

doi:10.1371/journal.pone.0312698

. 2024 Nov 7;19(11):e0312698. doi: 10.1371/journal.pone.0312698

Burden of mortality and its predictors among TB-HIV co-infected patients in Ethiopia: Systematic review and meta-analysis

Amare Kassaw ^1,^*, Demewoz Kefale ¹, Tigabu Munye Aytenew ², Molla Azmeraw ³, Muluken Chanie Agimas ⁴, Shegaw Zeleke ², Mastewal Ayehu Sinshaw ⁵, Nigatu Dessalegn ⁶, Worku Necho Asferie ⁷

Editor: Musa Mohammed Ali⁸

¹Department of Pediatrics and Child Health Nursing, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia

²Department of Adult Health Nursing, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia

³Department of Pediatrics and Child Health Nursing, College of Health Sciences, Woldia University, Woldia, Ethiopia

⁴Department of Epidemiology and Biostatics, Institute of Public Health, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

⁵Department of Nursing, Tibebe Gion Specialized Hospital, Bahir Bar University, Bahir Bar University, Bahir Dar, Ethiopia

⁶Department of Pediatrics and Child Health Nursing, College of Health Sciences, Injibara University, Injibara, Ethiopia

⁷Department of Maternal and Neonatal Health Nursing, College of Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia

⁸Hawassa University College of Medicine and Health Sciences, ETHIOPIA

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: amarekassaw2009@gmail.com

Roles

Amare Kassaw: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Software, Writing – original draft, Writing – review & editing

Demewoz Kefale: Data curation, Resources, Software, Writing – original draft, Writing – review & editing

Tigabu Munye Aytenew: Data curation, Methodology, Resources, Writing – original draft, Writing – review & editing

Molla Azmeraw: Funding acquisition, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing

Muluken Chanie Agimas: Data curation, Methodology, Resources, Validation, Writing – original draft, Writing – review & editing

Shegaw Zeleke: Conceptualization, Data curation, Resources, Supervision, Writing – original draft, Writing – review & editing

Mastewal Ayehu Sinshaw: Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

Nigatu Dessalegn: Investigation, Software, Writing – original draft, Writing – review & editing

Worku Necho Asferie: Data curation, Investigation, Project administration, Validation, Writing – original draft, Writing – review & editing

Musa Mohammed Ali: Editor

PMCID: PMC11542784 PMID: 39509354

Abstract

Background

Human immunodeficiency virus (HIV) and tuberculosis (TB) are still the two major deadly pandemics globally, causes 167,000 deaths in 2022. The two lethal combinations pose a substantial challenge to public health, especially in areas with high burden of both diseases such as Sub-Saharan Africa including Ethiopia. However, there is no study that showed national figure on mortality of TB/HIV co-infected patients. Hence, this review intended to provide pooled mortality rate and its predictors among patients co- infected with twin pandemics.

Methods

Using reputable electronic data bases, primary studies were searched from January 25 to February 5, 2024. The review included papers published in English language conducted between 2004 and 2024. Heterogeneity between included studies was evaluated using Cochrane Q-test and the I² statistics. Sub-group analysis was done to mitigate significant heterogeneity. Sensitivity analysis was also done to evaluate the effect of single studies on pooled estimated result.

Results

In this systematic review and meta-analysis a total of 5,210 study participants were included from 15 primary studies. The review disclosed that the pooled proportion and incidence of mortality were 18.73% (95% CI: 15.92-20.83) and 4.94 (95% CI: 2.98-6.89) respectively. Being bedridden and ambulatory functional status, poor ART adherence, CD4 count below the threshold (<200 cells/mm³), advanced WHO clinical staging, not provision of cotrimoxazole and isoniazid preventing therapy, anemia and extra pulmonary TB were significant predictors of mortality.

Conclusion and recommendations

The analyzed data of this systematic review and meta-analysis depicted that the national pooled proportion and incidence of mortality among TB-HIV co-infected patients were considered to be still high. The authors strongly recommended scale up and continuous provision of cotrimoxazole and isoniazid preventive therapy. In addition, early identification and treatment of anemia will greatly halt the high burden of mortality. Generally, to reduce mortality and improve survival, a collaborative effort is mandatory to emphasize close follow up of patients with identified predictors.

Introduction

Human immunodeficiency virus (HIV) and tuberculosis (TB) are the two major deadly pandemics worldwide [1–4]. According to World Health Organization (WHO) global report, about 214,000 in 2020 and 187,000 people in 2021 died due to TB-HIV co-infections [1, 5]. The organization also reported that the two lethal combinations have been the cause of 167,000 deaths in 2022. In the absence of appropriate treatment, nearly all TB-HIV co-infected patients will not survive [6]. Evidence showed that co-infection with HIV and TB accounted for roughly 40% of hospital deaths [7].

Both diseases are interacting in a complex and synergetic manner to influence one on other that leads to rapidly decrease the patients’ immunity system [8]. TB and HIV co- infection poses a substantial challenge to public health, especially in areas with high burden of both diseases such as Sub-Saharan Africa including Ethiopia [9]. HIV- infection weakens the immune system and makes the patient to be susceptible for tuberculosis infection and increase the progress from latent TB infection to active TB infection [10]. This weakened immune system gives a good opportunity for tuberculosis to progress rapidly and leads to more severe disease and increased risk of mortality and low survival [11]. TB infection also hastens the progress of HIV-infection by triggering an immune response that can increase HIV replication and viral load [10, 12]. The activation of immunity due to tuberculosis can induce inflammation and immune system dysfunction that alter the effectiveness of antiretroviral therapy [13].

Burden of mortality rate among TB-HIV co-infected patients is very high compared to having either disease alone [14, 15]. According to WHO, in 2017 the two pandemics attribute to the death of 300,000 people globally [16]. A finding from worldwide systematic review and meta-analysis revealed that the mortality of adults attributable to tuberculosis was 24.9% and 30.1% in children respectively [7]. The study conducted in china disclosed that the mortality rate among TB-HIV co-infected patients was 5.3% [17]. A similar study from China also showed that the mortality of patients co-infected with TB and HIV was 34.7% [18]. A cluster randomized trial study conducted in South Africa indicated that a mortality rate among TB-HIV co-infected patients was 10.1 per 100 person-years [19]. A study in Malaysia also depicted that the mortality of TB patients co-infected with HIV was 23.3% [20]. Evidence in Tanzania disclosed that the incidence of mortality among TB-HIV patients was 57.8 per 1000 person-years [11]. The risk of mortality is also high in Ethiopia among patients co-infected with these jeopardize infectious disease [21].

Several predicting factors were contributing for high mortality rate of patients with TB/HIV co- morbidities. From previous studies, the attributing factors of mortality among TB-HIV infected patients were low CD4 count [18, 22], WHO clinical stage 3 and 4 [23–25], ambulatory and bedridden functional status [26], being male gender [27], age of patients [28], residency [29, 30], missing of cotrimoxazole preventive therapy [30, 31] and not disclosing HIV status [32].

The globe has taken several measures to reduce the burden of morbidity and mortality due to TB-HIV co-infections as well as to eradicate in the near future. Joint United Nations Programme on HIV/AIDS (UNAIDS) is striving to end these two intertwined epidemics by 2030 through Fast Track and End TB Strategies [33]. TB/HIV collaborative activities undergone in in Latin America and the Caribbean countries have been scaled up and showed a tendency toward improvements [34]. Africa as a continent has straggled by setting Abuja declarations to end the pandemics by 2030 [35]. Ethiopia on its part has planned and implemented remarkable measures to tackle these catastrophic pandemics and to save million lives [21, 36]. Despite these interventions and successful achievements, TB/HIV co- infection is still the leading cause of death, particularly in resource limited settings [37, 38].

In Ethiopia several studies were conducted to show the high burden and incidence of death among patients as a result of TB-HIV co-infection and that indicated the mortality rate ranges from 12.3% in Southern Nation, Nationalities and Peoples Region (SNNPR) [39] and 35.39 in Amhara region [8]. The highest and the lowest incidence rate of mortality also found in Oromia [40] (14.56/100 person-years) and Tigray [41] (1.7/100 person-years) regions respectively. The finding showed that there is inconsistency and inconclusiveness among studies in different regions of the country. Therefore, the objective of this review was to determine the national level pooled mortality rate and its predictors among primary studies conducted on mortality of TB-HIV co- infected patients in Ethiopia.

Methods

Reporting

This review was done according to the preferred reporting systematic review and meta-analysis (PRISMA) guideline (S1 Checklist), and prospectively registered at the Prospero with a registration number of CRD42024511756.

Search strategy and study selection

Primary studies conducted in English were retrieved using international reputable electronic data bases. HINARI, PubMed, CINHAL, Scopus, web of science, Google scholar, Embase and Cochrane Library were systematically searched from January 25 to February 5, 2024. Open Google, university repositories and reference lists of eligible articles were also searched to find eligible articles. The eligible studies were accessed using the following search terms, keywords and Medical Subject Headings (MeSH terms): "Incidence"[Mesh], “incidence rate”, “incidence density”, magnitude, "Survival"[Mesh], "Mortality"[Mesh], predictors, “TB-HIV co-infection”, "Child"[Mesh], "Adult"[Mesh], "Persons"[Mesh], "Adolescent"[Mesh] and Ethiopia. The search terms and key words were combined using “AND” and “OR” Boolean operators to yield sufficient and appropriate search results (S1 Table). To access the eligible articles, the search was guided by the adapted PICO framework.

Eligibility criteria of studies

The search results of electronic search engine were exported to Endnote X8 software. Two authors (WNA and DK) were assigned to remove unrelated studies based on their title and abstract. They also screened full text articles according to pre-determined inclusion and exclusion criteria. Any arguments between the authors about eligibility of articles were disputed through discussion and interference of other reviewer members.

Inclusion and exclusion criteria

The authors have included studies conducted on mortality and its predictors among TB-HIV co-infected patients in Ethiopia. The review incorporated articles published in English language conducted between 2004 and 2024 since TB/HIV collaborative activities were piloted in 2004.Papers which do not report outcome interest and without full text articles were excluded. Additionally, studies conducted on multi-drug or extensively drug resistant tuberculosis and HIV co-infection as outcome interest were excluded (S2 Table).

Outcome measurement

The main outcome of this systematic review and meta-analysis was pooled proportion mortality rate among TB/ HIV co - infected patients. Pooled incidence mortality rate and its predictors were also other outcomes of the review.

Data extraction and screening process

AK and SZ screened the articles titles and abstracts against the inclusion and exclusion criteria. Then, relevant data were extracted by two reviewers (MA and TMA) according to predetermined exclusion and inclusion criteria from January 7 to 13/ 2024. Discrepancies between the authors were settled by discussion. First author name, publication year, study region, study design, study setting, sample size, outcome, response rate, incidence rate of mortality, mortality rate, predictors’ effect size (AHR) were extracted on Microsoft excel spread sheet (S1 Data).

Handling of missing data

The missing data were handled through complete case analysis method. There is no evidence to perform single or multiple imputation since the missing value is less than 5%.

Quality assessment

The Joanna Briggs Institute (JBI) quality assessment checklists for cohort studies were used to evaluate the quality of included studies. MCA and MAS were assigned to critical appraisal of the articles and disagreement between were resolved by other reviewers. The tool has the following criteria: appropriate statistical analysis used strategies to address incomplete follow up utilized, sufficient follow up time, measurement of the outcomes in a valid and reliable way, participants free of outcome at the beginning of the study, identifying confounding and strategies to reduce it. Accordingly, questions that fulfill the above criteria labeled as 1 and 0 for question that did not fulfill the criteria. Studies were considered to be low risk/high quality when scored 50% or higher on the quality assessment tools. Whereas, studies scored less than 49% on quality assessment checklist were categorized as high risk/low quality [42]. Therefore, in this systematic and met analysis all articles were scored greater than 50% (S2 Checklist).

Statistical analysis

After the data were extracted on Microsoft excel, exported to STATA version 17 statistical software for further analysis. The pooled mortality rate among TB- HIV co-infected patients and its predictors was estimated using random effects model using DerSimonian-Laird model weight. The presence of heterogeneity between included studies was evaluated using Cochrane Q-test and the I² statistics. Publication bias was checked through graphical (funnel plot) and statistical (Egger’s) test. Sub-group analysis was done to adjust random variation in the presence of significant heterogeneity between primary studies. A leave-one –out sensitivity analysis was done to evaluate the effect of single studies on pooled estimated result.

Operational definitions

Pooled proportion of mortality

pooled proportion of mortality is the ratio of the total death of patients co- infected with TB and HIV and the total case of patients infected with TB-HIV followed for a specified period of time.

Pooled incidence rate of mortality

The pooled incidence of mortality among TB-HIV co- infected patients is the mortality of an incident TB-HIV case, or event of interest which is the pooled result of mortality of new TB-HIV case during a given observation period/person-time observed.

Ethical consideration

Ethical clearance is not applicable for this systematic review and meta-analysis

Results

The search results of combined electronic data bases yield a total of 1051 articles. Of which, 388 studies were removed because of duplication. After careful reading of the titles and abstracts, 501 articles were also not retrieved. Again, 103 studies were removed as they reported unmatched outcome interest. Additionally, 44 articles were excluded after reading full text articles since studies not in Ethiopia, systematic reviews and other reasons. Finally, 15 studies were included for analysis of systematic review and meta-analysis (Fig 1).

Characteristics of included articles

In this systematic review and Mata analysis, fifteen primary studies [8, 26, 39–41, 43–52] with retrospective cohort study design were included to estimate the pooled mortality rate among patients with TB/HIV co –infection. Of these studies, only 10 articles [39–41, 43–45, 49–52] were used to determine the incidence of mortality rate. A total of 5,210 study participants were included with the smallest sample size (227) [44] from Amhara region and the maximum were from Oromia region (566) respectively [49]. Five studies were conducted in Oromia region [26, 40, 47, 48, 50], four in Amhara region [8, 43, 44, 49], three in SNNPRS [39, 45, 52] and 2 studies were done in Tigray region [41, 46] (Table 1).

Table 1. Characteristics of included studies among TB/HIV co-infected patients with outcomes.

First authors with publication year	Study region	Study design	Sample size	Mortality rate	IR/100PYO	Study quality
Atalel et al., 2018 [43]	Amhara	Retrosp. cohort	271	14.02	3.27	Low risk
Birhan et al., 2021 [8]	Amhara	Retrosp. cohort	243	35.39		Low risk
Chanie et al., 2021 [44]	Amhara	Retrosp. cohort	227	17.18	3.7	Low risk
Dawit et al., 2021 [45]	SNNPRS	Retrosp. cohort	274	17.15	2.97	Low risk
Gemechu et al., 2022 [39]	SNNPRS	Retrosp. cohort	284	12.3	2.78	Low risk
Gesesew et al., 2016 [26]	Oromia	Retrosp. cohort	272	20.2		Low risk
Gezea et al., 2020 [46]	Tigray	Retrosp. cohort	305	23		Low risk
Habtegiorgis et al., 2023 [47]	Oromia	Retrosp. cohort	471	16.8		Low risk
Lelisho et al., 2022 [40]	Oromia	Retrosp. cohort	402	20.9	14.56	Low risk
Nigussie et al., 2021 [41]	Tigray	Retrosp. cohort	253	15	1.7	Low risk
Refera et al., 2013 [48]	Oromia	Retrosp. cohort	501	15.8		Low risk
Silesh et al., 2013 [49]	Amhara	Retrosp. cohort	422	22.04	4.09	Low risk
Sime et al., 2022 [50]	Oromia	Retrosp. cohort	566	13.4	11.04	Low risk
Teklu et al., 2017 [51]	Ethiopia	Retrosp. cohort	355	14	2.5	Low risk
Wondimu et al., 2020 [52]	SNNPRS	Retrosp. cohort	364	22.8	5.02	Low risk

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Pooled proportion mortality rate of TB/HIV co-infected patients in Ethiopia

A total of 15 studies [8, 26, 39–41, 43–52] were used to estimate the pooled proportion mortality rate of patients co-infected with TB/HIV. Based on the random effects model, the mortality rate was 18.73% (95% CI: 15.92-20.83) with significant heterogeneity (I2=82.12%) (Fig 2).

Ten studies were also used to estimate the pooled incidence mortality rate among TB-HIV co-infected patients. Accordingly, the overall pooled incidence mortality rate was 4.94 (95% CI: 2.98-6.89) with substantial heterogeneity (I²= 88.72%) (Fig 3).

Handling heterogeneity

To handle the observed heterogeneity, sub-group and sensitivity analysis were carried out on mortality rate and incidence density mortality rate among TB/HIV co-infected patients. Sub-group analysis was performed using publication year, region, sample size and age of patients. Based on this, mortality of patients was high among studies conducted after 2020 as compared to studies done before 2020 (Fig 4). Sub-group analysis concerning to region, the highest proportion of mortality rate was found in Amhara region followed by Tigray regional state (S1 Fig). Mortality rate among patients age greater than 15 years (adults) was higher as compared to their counterparts (S2 Fig). Similarly, mortality rate among TB/HIV co-infected patients with sample size less than 350 was higher compared to studies with sample size greater than 350 (Fig 5).

Regarding to sub-group analysis of incidence of mortality rate, studies conducted exclusively on adult patients has higher incidence of mortality rate than studies done on children (S3 Fig). Based on the region, the highest incidence of mortality was also observed in Oromia region followed by Amhara region (S4 Fig). Likewise, the new occurrence of mortality was greater among studies published after the year 2020 than before 2020 (S5 Fig).

Sensitivity analysis and publication bias

The result of leave-one out sensitivity analysis showed that there is no single study that excessively affects the pooled estimated effect of mortality among TB-HIV co-infected patients (Fig 6). To identity publication bias, we performed statistical test (Eggers’ test) and visual inspection (funnel plot). The graphical presentation of funnel plot showed that there is symmetrical distribution of studies. Hence, this declares there is no small study effect (S6 Fig). Similarly, Eggers’ statistical test analysis revealed that there is no publication bias since p-value is insignificant (p-value=0.74).

Pooled effects of predictors on the mortality of patients co- infected with TB/HIV

We conducted meta- analysis to determine the pooled effects of predictors of mortality among TB/HIV co-infected patients. Bedridden and ambulatory functional status, poor ART adherence, CD4 count below the threshold (<200 cells/mm³), advanced WHO clinical staging, missing of cotrimoxazole and isoniazid preventing therapy, anemia, and extra pulmonary TB were significant predictors of mortality (Table 2).

Table 2. The pooled effects of predictors on mortality of TB/HIV-infected patients in Ethiopia.

Variables	Variable Categories	Included studies	AHR (95% CI)	Heterogeneity)I2%, P-value)	Egger’s P-value
ART adherence	Fair &poor	4	3.88(2.890-4.88)	77.86, 0.001	0.8007
ART adherence	Good		1
CD4 count	Below threshold	5	3.48(1.74-5.22)	97.49, 0.001	0.1971
CD4 count	Above threshold		1
Taking CPT	No	7	2.73(2.12-3.33)	85.04, 0.001	0.5411
Taking CPT	Yes		1
Anemia	Yes	3	2.80(2.23-3.37)	27.08, 0.001	0.765
Anemia	No		1
Taking IPT	No	4	3.10(2.72- 3.48)	0.00, 0.001	0.9681
Taking IPT	Yes		1
Bedridden	Yes	5	3.30(2.07- 4.53)	93.43, 0.001	0.6531
Bedridden	No		1
Ambulatory	Yes	2	2.08(1.658-2.49)	0.00, 0.001	0.9412
Ambulatory	No		1
WHO stages III	Stage III	3	2.98(2.51-3.46)	0.001, 0.001	0.9376
WHO stages III	Stage I & II		1
WHO stages IV	Stage IV	7	4.17(3.28-5.06)	84.01, 0.001	0.0183
WHO stages IV	Stage I & II		1
Extra PTB	Yes	8	2.56(1.36-3.76)	95.79, 0.001	0.9986
	No		1

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Four studies [39, 41, 43, 45] were used to assess the association of poor ART adherence and mortality of patients co-infected with TB/HIV. A random effects model analysis indicated that patients with poor and fair ART adherence had 3.88 (AHR=3.88; 95%CI: 2.890-4.88) times hazard to death than good adherence. Similarly, patients with low CD4 count were 3.48 times (AHR=3.48; 95%CI: 1.74-5.22) more likely to die compared to their counterparts.

A total seven studies [40, 43, 44, 46, 47, 49, 52] were combined to determine the association of cotrimoxazole preventing therapy and mortality of TB/HIV co-infected patients. Significant heterogeneity were observed among studies (I²=97.49%, p-value<0.001). Leave-one –out sensitivity analysis showed that there is no single study that affects the result of pooled estimated effect (S7 Fig). Egger’s statistical test evidenced that there is no publication bias among studies (P-value=0.5411).

Bedridden patients had 3.30 times hazard to death (AHR=3.30: 95%CI: 2.07- 4.53) as compared to their counterparts with substantial heterogeneity among included studies (I²=93.43%, P-value<0.001). The analysis results of random effects model disclosed that there is no a single study that excessively affect the overall estimated result (S8 Fig) and also there is no evidence of small study effect among studies (p-value= 0.6531).

Seven primary studies [26, 39–41, 47, 48, 50] were used to identify the pooled effects of association between WHO clinical stage IV and mortality of patients with TB/HIV co-infection. A random effects model analysis indicated that TB/HIV co-infected patients who had WHO stage IV were about 4 times hazard to death (AHR=4.17; 95%CI:3.28-5.06) than stage I and Stage II. There was significant heterogeneity among included studies (I²=84.01%, p-value=0.001). From sensitivity analysis, no single study affects the pooled estimated finding (S9 Fig).

Likewise, eight studies [39, 41, 43, 45–49] were used to identify the pooled estimated effect of the association between extra pulmonary tuberculosis and mortality of TB/HIV co-infected patients. Patients with extra PTB were 2.56 (AHR=2.56; 95%CI: 1.36-3.76) times more likely to die than PTB patients. Leave-one –out sensitivity analysis showed that there is no a single study that affect the result of pooled estimate (S10 Fig) with no small study effect (Eggers’ p-value=0.9986) (Table 2).

Discussion

Despite high scale up of anti-TB and antiretroviral therapy, HIV and tuberculosis remain the leading causes of death in TB/ HIV co-infected persons, particularly in middle and low income countries [18, 38]. This systematic review and meta-analysis aimed to estimate the national level pooled mortality rate and its predicting variables using 15 primary studies among TB/HIV co-infected patients in Ethiopia.

The review finding disclosed that the pooled mortality rate was 18.73% (95% CI: 15.92-20.83). This result was higher than primary studies conducted in Uganda [53], Conakry [54], Nigeria [55], Myanmar [56], South Africa [57] and Botswana [37]. The possible reason might be socio-economic status, study populations, methodological difference (meta-analysis versus primary studies). Most importantly, study time difference because of studies conducted before OVID-19 has low mortality rate than studies done after COVID-19. It is known that the epidemic has interrupted predetermined plans and interventions even the existing ART and anti-TB treatments were endangered during the catastrophic pandemic [58]. However, the finding was lower than the following studies: a systematic review and meta-analyses conducted in low and middle income countries [38], a cohort study conducted in China [18], a finding in Malaysia [20], a randomized trial in Cambodia [59], in Brazil [60] and worldwide systematic review and meta-analysis [7]. The discrepancy might be due to socio-demographic, studies period and culture differences among populations. The other justification might be introduction and strictly adherence of ART and TB treatment guidelines [21].

This systematic review and meta-analysis also revealed that the pooled incidence mortality rate was 4.94 (95% CI: 2.98-6.89). This result is lower than primary studies conducted in Tanzania [61], Cambodia [59], Uganda [62] and Cameroon [63].While the finding was higher than studies in Nigeria [64] and in South Africa [65]. The plausible reason for this discrepancy might be socio-cultural and economical differences, study time and sample size variation. Additionally, the current study is mixed with adult and children populations and as a result used different methodology might be the reason for inconsistency.

The result of sub-group analysis based on region evidenced that the highest proportion of mortality rate was found in Amhara region followed by Tigray regional state. This might be because of regional variation of care provided for TB/HIV co-infected patients. The other justification would be due to sample size, study follow up time and types of populations studied. The proportion of mortality was higher among patients greater than age 15 and above compared to their counterparts which is supported by the result of systematic review and meta-analysis evidence [15]. This is the fact that opportunistic infection including TB are occur frequently and in severe form in adults which leads to higher proportion of morbidity and mortality [66]. In a similarly way, mortality of patients was high among studies conducted after 2020 as compared to studies done before 2020.This is the fact that after the era of COVID-19, it impose a triple burden on the quality of health service management [67] and has fallen tremendous impact on the control measures of HIV and tuberculosis infections [68, 69].

The current review indicated that patients with poor ART adherence were about four times more likely to die than patients with good adherence status. Studies in Cameroon and Ethiopia [70, 71] had support this evidence. It is kwon that antiretroviral therapy (ART) transforms and improves the life span of persons with HIV and other opportunistic infections by sustain viral suppression and restrain viral replication and, saving the from depletion of the immune system that accelerate the death of patients [72]. No adherence to ART follows drug resistance, treatment failure and exposed the patients to second line ART regimens which results poor patient progress, increase health care costs and reduce survival [73].

TB/HIV co-infected patients with low CD4 count (<200ell/mm³) were nearly 3.5 times more hazard to death than patients with normal threshold of CD4 count. This is in agreement with the finding in Tanzania [61], Nigeria [64], Caribbean, Central and South America, and Central, East, and West Africa [74], China [75] and Malaysia [20]. Evidences suggested that HIV causes immunosuppression directly by depletion of host CD4⁺ T-cells that increase the vulnerability of active TB infection [76] that leads to dramatically fasten the death of persons co-infected with the two worst pandemics [77].

Likewise, patients with low hemoglobin level (<10mg/dl) were more likely to die than their counterparts. It is congruent of previous finding of remember clinical trial study [78] and studies in Ethiopia [79]. Anemia in TB/HIV co-infected patients causes treatment failure, lost to follow up and death [80]. It also increase viral load, decrease CD4 count, progress HIV to advanced stage, chronic inflammation and all cause of mortality [81]. Similarly, the current review depicted that TB/HIV co-infected patients with advanced WHO stage were about 4 times hazard to death compared to their counterparts. This is in line with the study done in Tanzania [11, 61] and Malawi [82]. As HIV progress to advanced stage, the patient would be more affected by variety of opportunistic infections, depressed immunity system which further complicated the scenario and decreases survival of TB/HIV co-infected patients [83, 84].

Patients with extra pulmonary tuberculosis were more likely to die than patients with pulmonary tuberculosis which is similar studies in Cameroon [63] and a systematic review elsewhere [85]. Extra pulmonary tuberculosis is the commonest manifestation and leading cause of in HIV-infected patients, particularly in advanced stage of the disease [86]. Extra pulmonary tuberculosis is poorly recognized and which resulted delayed diagnosis and treatment than pulmonary TB and leads to low survival and increase mortality rate [87].

Consistent with the previous literature, this systematic review and meta-analysis also showed that TB/HIV-infected subjects who missing of cotrimoxazole and isoniazid preventing therapy were contribute more hazards to death [88]. Studies reasoned that Isoniazid Preventing Therapy minimize the risk of reactivation of latent TB infection in HIV infected individuals by decreasing mycobacterium load [89]. Cotrimoxazole Preventing Therapy (CPT) also highly prevents suffering and mortality from TB/HIV-co infections [90]. The plausible justification is that CPT can reduce the developments of pneumocystis jirovecii pneumonia which is the main cause of mortality in advanced disease of HIV [91].

The review evidenced that study subjects with bedridden functional status were more hazard to death compared to their counterparts. Bedridden patients were more victimized for immune suppression, severe and complicated opportunistic infections and further deterioration of their health status and fasten the rate of dying [92].

Strength and limitation of the review

Sensitivity and sub-group analysis was performed to investigate heterogeneity among studies. The included articles with similar study design (cohort) which better identifies cause and effect relationship and reduce methodological variability. Even if the aforementioned strength, the review has its own drawbacks: Qualitative studies and articles published other than English language was excluded. We could not access primary studies from all regions of Ethiopia and some of the included articles also had small sample size that might affect the true pooled estimated result. Due to the nature of meta-analysis, confounding variables that might affect the mortality of TB/HIV co-infected patients were not investigated.

Conclusion

The analyzed data of this systematic review and meta-analysis depicted that the national pooled proportion and incidence of mortality among TB-HIV co-infected patients were considered to be still high. Being bedridden and ambulatory functional status, poor ART adherence, CD4 count below the threshold (<200 cells/mm³), advanced WHO clinical staging, missing of cotrimoxazole and isoniazid preventing therapy, anemia and extra pulmonary TB were significant predictors of mortality. The authors strongly recommended scale up and continuous provision of cotrimoxazole and isoniazid preventive therapy. In addition, early identification and treatment of anemia will greatly halt the high burden of mortality. In general to reduce mortality, morbidity and improve survival, a collaborative effort is mandatory to emphasize close follow up of patients with identified predictors.

Supporting information

S1 Checklist. PRISMA 2020 checklist for included studies.

(DOCX)

pone.0312698.s001.docx^{(32.4KB, docx)}

S2 Checklist. JBI critical appraisal checklist for included articles.

(DOCX)

pone.0312698.s002.docx^{(19.2KB, docx)}

S1 Data. Extracted data set from included studies.

(RAR)

pone.0312698.s003.rar^{(103.8KB, rar)}

S1 Table. Search strategies and entry terms from electronic data bases on mortality and its Predictors among TB-HIV co-infected patients in Ethiopia: Systematic and meta-analysis.

(DOCX)

pone.0312698.s004.docx^{(18KB, docx)}

S2 Table. List of excluded studies.

(DOCX)

pone.0312698.s005.docx^{(282.6KB, docx)}

S1 Fig. Forest plot of regional sub-group analysis on mortality rate among TB/HIV co-infected patients.

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S2 Fig. Forest plot of sub-group analysis based on age on mortality rate among TB/HIV co-infected patients.

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S3 Fig. Forest plot of sub-group analysis based on age on incidence of mortality rate among TB/HIV co-infected patients.

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S4 Fig. Forest plot of regional sub-group analysis on incidence of mortality rate among TB/HIV co-infected patients.

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S5 Fig. Forest plot of sub-group analysis according to publication year on incidence of mortality rate among TB/HIV co-infected patients in Ethiopia.

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S6 Fig. Funnel plot to show publication bias of the included studies.

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S7 Fig. Leave-one –out sensitivity analysis of CPT on mortality of among TB/HIV co-infected patients.

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S8 Fig. Leave-one –out sensitivity analysis of factor bedridden on mortality of among TB/HIV co-infected patients.

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S9 Fig. Leave-one –out sensitivity analysis of WHO stage IV on mortality of among TB/HIV co-infected patients.

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S10 Fig. Leave-one –out sensitivity analysis of extra PTB on mortality of among TB/HIV co-infected patients.

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pone.0312698.s015.tif^{(289.9KB, tif)}

Acknowledgments

The authors are pleased to acknowledge Deber Tabor University for supplementary materials and support to conduct this Review. We also extend our thanks to the authors of included articles in this systematic review and meta-analysis. Last but not least, we acknowledged Bahir Dar University College of health sciences for allowing internet service.

Abbreviations

HIV: Humane Immune Virus
AIDS: Acquired Immune Deficiency Virus
HAART: Highly Active Antiretroviral Therapy
ART: Antiretroviral Therapy
AHR: Adjusted Hazard Ratio
CI: Confidence Interval
TB: Tuberculosis
PTB: Pulmonary tuberculosis
IPT: Isoniazid preventive therapy
CPT: Cotrimoxazole preventive therapy
WHO: World Health Organization

Data Availability

All relevant data are within the article and its supporting information files.

Funding Statement

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

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PLoS One. doi: 10.1371/journal.pone.0312698.r001

Decision Letter 0

Musa Mohammed Ali

16 Sep 2024

PONE-D-24-10192Burden of mortality and its Predictors among TB-HIV co-infected patients in Ethiopia: systematic review and Meta-analysis.PLOS ONE

Dear Dr. Kassaw,

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Musa Mohammed Ali, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: Yes

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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: No

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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)

Reviewer #1: Some minor error in the construction of paragraphs. The author must revise some repetitions for example 2024. As a systematic review and met analysis I think that all the parts of this types of study has been completed. The aims of the paper has been reached. The introduction gives a summary of the causes of death in the region and globally, specifically for human immunodeficiency infection and tuberculosis. The review disclosed that the pooled proportion and incidence of mortality were 18.73% (95% CI: 15.92-20.83) and 4.94 (95% CI: 2.98-6.89) respectively. Being bedridden and ambulatory functional status, poor ART adherence, CD4 count below the threshold (<200 cells/mm3), advanced WHO clinical staging, not provision of cotrimoxazole and isoniazid preventing therapy, anemia and extra pulmonary TB were significant predictors of mortality. The results reports or are in agreement with the conclusions of the study. It is the first systematic review of its kind done in the country. Should take this in consideration in doing a final assessment of its suitability for acceptance.

Reviewer #2: This study addresses important questions related to the double burden of HIV and TB in Ethiopia. It explores the burden of mortality from HIV and TB co-infection over the past 20 years, offering a better understanding of the predictors of mortality among individuals co-infected with HIV and TB in Ethiopia.

Minor comments

1. Acronyms - The authors can improve clarity by introducing the full term followed by its abbreviation when first mentioned, and then consistently using the acronym in subsequent references, rather than repeating the full term.

2. To ensure consistent formatting, the authors should address some issues. In the discussion section, the word 'REMEMBER' is in capital letters and should be corrected to lowercase. Additionally, 'S7 Figure' is highlighted in red in the results section, which needs adjustment. Lastly, one of the lines in Figure 1 of the results section requires fixing for clarity.

Major comments

1. There appears to be a lack of consistency in the naming of the outcome measures. For instance, the methods section refers to the outcome measures as 'pooled mortality rate' and 'pooled incidence mortality rate,' while the results section uses the term 'incidence density mortality rate.' Additionally, the term 'pooled proportion' is used in the conclusion. It is important to ensure consistency in the terminology used for the outcome measures throughout the manuscript.

It would be helpful to include definitions for the two outcome measures in the methods section and to explain how they were calculated. This could involve specifying both the numerator and denominator for each outcome to ensure clarity and consistency.

2. The manuscript would benefit from thorough proofreading and editing to enhance clarity and accuracy.

3. In the methods section of the abstract, authors may not need to mention the quality assessment of primary studies or publication bias; these details could be reserved for the methods section of the manuscript. Instead, the abstract should include the number of papers included in the systematic review and meta-analysis, the duration of the search period (from 2004 to 2024), and the total sample size. Additionally, specify the analyses performed with the data extracted from the primary studies, including any subgroup analyses conducted by region.

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Reviewer #1: Yes: Angel Vaillant

Reviewer #2: No

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PLoS One. 2024 Nov 7;19(11):e0312698. doi: 10.1371/journal.pone.0312698.r002

Author response to Decision Letter 0

26 Sep 2024

Response to Reviewers and editor

Point by point responses

We would like to take this opportunity to thank the reviewers and editor for sharing their view and constructive comments. The comments were very important which further improves the quality of our manuscript. The point-by-point responses for each of the comments are provided in the following pages. Our responses are written in blue font color.

# Journal requirements

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming

Authors’ Response

We are grateful to this comment of technical relevance. Thus, we have ensured that our manuscript meets PLOS ONE's style requirements, including those for file naming

Authors’ Response

We accept the comment and remove all personal information (Search date and location) and re-upload the data.

3. 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.

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’ Response

Thank you for this concern. We clearly put this concern in figure one that showed all studies identified in the literature search including those that were excluded from the analyses with reasons of exclusion.

Accepting the comment, we have put the extracted data on (S1 data) of supporting information on the revised manuscript. The date and the names of the data extractors were include on the main document of the revised version of this manuscript. The eligibility of the include studies were assessed on the quality assessment part of methods section.

As detailed in the methods sections, the pooled mortality rate among TB- HIV co-infected patients and its predictors was estimated using random effects model using DerSimonian-Laird model weight by utilizing Stata 17 statistical software.

Regarding to how missing data were handled, an explanation is done on the revised manuscript (page 6).

Authors’ Response

The authors are very grateful of these constructive comments. After read the reference lists carefully, we made some correction and addressed the incomplete one. We are sure that we have not cited retracted references, almost all references are recent.

Response to Reviewer #1 comments

5. Some minor error in the construction of paragraphs. The author must revise some repetitions for example 2024. As a systematic review and meta-analysis I think that all the parts of this types of study has been completed…..the aims of the paper have been reached the results reports or are in agreement with the conclusions of the study. It is the first systematic review of its kind done in the country. Should take this in consideration in doing a final assessment of its suitability for acceptance.

Authors’ Response

First of all, we really thank the reviewer for his constructive comments and suggestions. The authors have accepted the comments and corrected it in the revised version of the manuscript

Reviewer #2:

Minor comments

Authors’ Response

Dear reviewer, we want to say thank you very much for your relevant, constructive and detail comments and suggestions that have a great value to improve our manuscript. The comment is taken and corrected accordingly.

2. To ensure consistent formatting, the authors should address some issues. In the discussion section, the words ‘REMEMBER' is in capital letters and should be corrected to lowercase. Additionally, 'S7 Figure' is highlighted in red in the results section, which needs adjustment. Lastly, one of the lines in Figure 1 of the results section requires fixing for clarity

Authors’ Response

Thank you and we corrected it.

Major comments

Authors’ Response

Based on the comment, correction is made on the revised version of the manuscript.

2. The manuscript would benefit from thorough proofreading and editing to enhance clarity and accuracy.

Authors’ Response

Thank you for your constructive comments. After we have read carefully through the whole document, we properly addressed the concerned issues.

Accepting the comment, the authors have read thoroughly and edited carefully the whole manuscript before submission.

Authors’ Response

Accepting the comment, the authors have corrected accordingly.

4. Additionally, specify the analyses performed with the data extracted from the primary studies, including any subgroup analyses conducted by region.

Authors’ Response

After we extracted the data from primary studies on Microsoft excel, the analysis was performed by using STATA 17 statistical software. Then, the pooled mortality rate among TB- HIV co-infected patients and its predictors was estimated using random effects model using DerSimonian-Laird model weight.

Sub-group analysis was also performed using publication year, region, sample size and age of patients from the extracted data and presented using frost plot.

Attachment

Submitted filename: Response to reviewers.pdf

pone.0312698.s016.pdf^{(381.9KB, pdf)}

PLoS One. doi: 10.1371/journal.pone.0312698.r003

Decision Letter 1

Musa Mohammed Ali

11 Oct 2024

Burden of mortality and its Predictors among TB-HIV co-infected patients in Ethiopia: systematic review and Meta-analysis.

PONE-D-24-10192R1

Dear Dr. Kassaw,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Musa Mohammed Ali, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: 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

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: (No Response)

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6. Review Comments to the Author

Reviewer #1: The authors have carefully addressed all the comments raised during the peer review process. After thorough revisions, the research work appears accurate and unbiased.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (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: Yes: Dr. Angel Vaillant

Reviewer #2: No

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PLoS One. doi: 10.1371/journal.pone.0312698.r004

Acceptance letter

Musa Mohammed Ali

24 Oct 2024

PONE-D-24-10192R1

PLOS ONE

Dear Dr. Kassaw,

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:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Musa Mohammed Ali

Academic Editor

PLOS ONE

Associated Data

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

Supplementary Materials

S1 Checklist. PRISMA 2020 checklist for included studies.

(DOCX)

pone.0312698.s001.docx^{(32.4KB, docx)}

S2 Checklist. JBI critical appraisal checklist for included articles.

(DOCX)

pone.0312698.s002.docx^{(19.2KB, docx)}

S1 Data. Extracted data set from included studies.

(RAR)

pone.0312698.s003.rar^{(103.8KB, rar)}

S1 Table. Search strategies and entry terms from electronic data bases on mortality and its Predictors among TB-HIV co-infected patients in Ethiopia: Systematic and meta-analysis.

(DOCX)

pone.0312698.s004.docx^{(18KB, docx)}

S2 Table. List of excluded studies.

(DOCX)

pone.0312698.s005.docx^{(282.6KB, docx)}

S1 Fig. Forest plot of regional sub-group analysis on mortality rate among TB/HIV co-infected patients.

(TIF)

pone.0312698.s006.tif^{(690.5KB, tif)}

S2 Fig. Forest plot of sub-group analysis based on age on mortality rate among TB/HIV co-infected patients.

(TIF)

pone.0312698.s007.tif^{(682.9KB, tif)}

S3 Fig. Forest plot of sub-group analysis based on age on incidence of mortality rate among TB/HIV co-infected patients.

(TIF)

pone.0312698.s008.tif^{(582.4KB, tif)}

S4 Fig. Forest plot of regional sub-group analysis on incidence of mortality rate among TB/HIV co-infected patients.

(TIF)

pone.0312698.s009.tif^{(626.1KB, tif)}

S5 Fig. Forest plot of sub-group analysis according to publication year on incidence of mortality rate among TB/HIV co-infected patients in Ethiopia.

(TIF)

pone.0312698.s010.tif^{(524KB, tif)}

S6 Fig. Funnel plot to show publication bias of the included studies.

(TIF)

pone.0312698.s011.tif^{(258.3KB, tif)}

S7 Fig. Leave-one –out sensitivity analysis of CPT on mortality of among TB/HIV co-infected patients.

(TIF)

pone.0312698.s012.tif^{(259.5KB, tif)}

S8 Fig. Leave-one –out sensitivity analysis of factor bedridden on mortality of among TB/HIV co-infected patients.

(TIF)

pone.0312698.s013.tif^{(274.3KB, tif)}

S9 Fig. Leave-one –out sensitivity analysis of WHO stage IV on mortality of among TB/HIV co-infected patients.

(TIF)

pone.0312698.s014.tif^{(270.6KB, tif)}

S10 Fig. Leave-one –out sensitivity analysis of extra PTB on mortality of among TB/HIV co-infected patients.

(TIF)

pone.0312698.s015.tif^{(289.9KB, tif)}

Attachment

Submitted filename: Response to reviewers.pdf

pone.0312698.s016.pdf^{(381.9KB, pdf)}

Data Availability Statement

All relevant data are within the article and its supporting information files.

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PERMALINK

Burden of mortality and its predictors among TB-HIV co-infected patients in Ethiopia: Systematic review and meta-analysis

Amare Kassaw

Demewoz Kefale

Tigabu Munye Aytenew

Molla Azmeraw

Muluken Chanie Agimas

Shegaw Zeleke

Mastewal Ayehu Sinshaw

Nigatu Dessalegn

Worku Necho Asferie

Roles

Abstract

Background

Methods

Results

Conclusion and recommendations

Introduction

Methods

Reporting

Search strategy and study selection

Eligibility criteria of studies

Inclusion and exclusion criteria

Outcome measurement

Data extraction and screening process

Handling of missing data

Quality assessment

Statistical analysis

Operational definitions

Pooled proportion of mortality

Pooled incidence rate of mortality

Ethical consideration

Results

Fig 1. PRISMA2020 flow diagram of article selection for systematic review and meta-analysis of mortality among TB-HIV co-infected patients in Ethiopia.

Characteristics of included articles

Table 1. Characteristics of included studies among TB/HIV co-infected patients with outcomes.

Pooled proportion mortality rate of TB/HIV co-infected patients in Ethiopia

Fig 2. Forest plot showing the pooled mortality rate of patients co-infected with TB/HIV.

Fig 3. Forest plot on pooled incidence mortality rate of patients co-infected with TB/HIV.

Handling heterogeneity

Fig 4. Forest plot of sub-group analysis according to publication year on mortality rate among TB/HIV co-infected patients in Ethiopia.

Fig 5. Forest plot showing sub-group analysis based on sample size on mortality rate among TB/HIV co-infected patients in Ethiopia.

Sensitivity analysis and publication bias

Fig 6. Leave-one out sensitivity analysis of mortality among TB/HIV co-infected patients in Ethiopia.

Pooled effects of predictors on the mortality of patients co- infected with TB/HIV

Table 2. The pooled effects of predictors on mortality of TB/HIV-infected patients in Ethiopia.

Discussion

Strength and limitation of the review

Conclusion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Musa Mohammed Ali

Roles

Author response to Decision Letter 0

Decision Letter 1

Musa Mohammed Ali

Roles

Acceptance letter

Musa Mohammed Ali

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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