Skip to main content
NCBI home page
PLOS One logoLink to PLOS One
. 2023 Oct 24;18(10):e0286476. doi: 10.1371/journal.pone.0286476

Prevalence of delayed antiretroviral therapy initiation among people living with HIV: A systematic review and meta-analysis

Yan Tao 1, Xueling Xiao 1, Ci Zhang 1, Ying Xie 1, Honghong Wang 1,*
Editor: Lara Vojnov2
PMCID: PMC10597480  PMID: 37874794

Abstract

Objective

HIV continues to be a global challenge. Key recommendations for HIV prevention and treatment are presented on rapid antiretroviral therapy (ART) initiation. However, several studies showed a high prevalence of delayed ART initiation. The aim of this systematic review and meta-analysis was to assess the prevalence of delayed ART initiation among HIV-infected patients globally.

Methods

This review summarised eligible studies conducted between January 2015 and August 2022 on the prevalence of delayed ART initiation in HIV-infected adults (age ≥ 15). Relevant studies were systematic searched through PubMed/Medline, EMBASE, Web of Science, China National Knowledge Infrastructure, Wanfang, and Chongqing VIP databases. Random-effects models were used to calculate pooled prevalence estimates. The heterogeneity was evaluated using Cochran’s Q test and I2 statistics. Moreover, potential sources of heterogeneity were explored using univariate subgroup analysis.

Results

Data on the prevalence of delayed ART initiation was pooled across 29 studies involving 34,937 participants from 15 countries. The overall pooled prevalence of delayed ART initiation was 36.1% [95% confidence interval (CI), 29.7–42.5%]. In subgroup analysis, the estimated pooled prevalence decreased with age. By sex, the prevalence was higher among male patients (39.3%, 95% CI: 32.2–46.4%) than female (36.5%, 95% CI: 26.9–50.7%). Patients with high CD4 cell count were more likely to delay ART initiation than those with low CD4 cell count (>500cells/mm3: 40.3%; 201-500cells/mm3: 33.4%; and ≤200cells/mm3: 25.3%).

Conclusions

Our systematic review and meta-analysis identified a high prevalence of delayed ART initiation. The prolonged time interval between diagnosis and treatment is a prevalent and unaddressed problem that should spur initiatives from countries globally. Further research is urgently needed to identify effective strategies for promoting the early ART initiation.

Introduction

HIV remains the leading cause of death and disability worldwide, endangering the health of the population and increasing the economic cost to health systems. By the end of 2021, 38.4 million people globally were infected with HIV, and 40.1 million people have died from AIDS-related diseases since the beginning of the epidemic [1]. Antiretroviral therapy (ART) is highly effective in slowing the progression of HIV to AIDS, reducing AIDS-related mortality and morbidity [2, 3], and preventing further HIV transmission, as achieving undetectable virus means nontransmissible virus [4, 5]; thus, timely initiation and full coverage of ART is necessary. However, only 87% of those who know their status have initiated ART, which is far from achieving the second ‘95’ of the UNAIDS ‘95-95-95’ target by 2025 [1, 6].

Early initiation of treatment after diagnosis maximizes the benefits of ART at the individual and population levels. Randomized controlled trials in Uganda and South Africa demonstrated the feasibility and improvement in terms of treatment coverage and retention rates over three months with same-day initiation of ART, compared to the standard initiation group [7, 8]. The HPTN 052 trial in nine African countries clearly showed that early initiation of ART with CD4 counts between 350 and 550 cells /mm3 facilitated the faster achievement of viral load suppression and reduced HIV transmission by approximately 96% compared to late ART initiation with CD4 count < 250 cells /mm3 [9]. Observational studies conducted in South Africa [10], Eswatini [11] and Ethiopia [12], which compared early treatment with standard care, reported similar results. Moreover, if ART is initiated immediately, the cost of hospitalization may be minimized in resource-poor and HIV-prone prevalence countries [13, 14]. As a result of this evidence, the World Health Organization (WHO) recommended in 2015 that all HIV-infected patients should start ART once they are diagnosed with HIV, regardless of stage of disease and CD4 cell count (known as “treat all”). There is no reason to delay treatment decisions based on CD4 cell threshold [15, 16].

However, despite knowing the benefits of early treatment and the expanding ART eligibility criteria, delayed initiation of ART persists and some countries face challenges in reaching the ‘95-95-95’ targets [1]. A retrospective study reviewing the rate of ART initiation in HIV-infected ART-naive women in Uganda, revealed delayed treatment rates of up to 72% [17]. Wei et al. analyzed the timeliness of ART initiation in newly reported HIV-infected patients in Hunan Province, China, from 2014 to 2018, suggesting that 58% of patients did not initiate ART within one month of diagnosis [18]. A pilot randomized controlled trial from 2015 to 2016 indicated that 67% of HIV-infected adults were linked to care and 42% initiated ART within three months of referral for treatment [19]. A systematic review of HIV care retention has shown that the longer lag time between testing and treatment, the higher the rate of patients lost to ART care [20]. Taking these studies together, reliable estimates of delayed ART initiation after the introduction of the “treat all” strategy and understanding various potential related factors are essential for informing ongoing and future intervention strategies to effectively improve coverage of ART.

In general, there is no unified, clear, evidence-based definition of delayed initiation of treatment. Various delayed ART initiation for time to ART initiation have been used in the studies, such as time from diagnosis to ART initiation, time from first clinical visit to ART initiation [21], time from eligibility to ART initiation [22], and time from enrolment in HIV care to ART initiation [23]. Time from HIV diagnosis to commencement of ART was proposed as a more feasible and sensitive indicator of ART uptake [24]. In our study, delayed ART initiation was defined as failure to initiate ART within 30 days of confirmation of HIV diagnosis, as previous studies have found that one month was sufficient for most patients to complete the steps needed to start treatment under routine care [25, 26].

To the best of our knowledge, there are no current or ongoing systematic reviews of the prevalence of delayed ART initiation, although sufficient data exist to make pooled estimates and to explore the source of heterogeneity between studies through meta-analysis. To fill this critical gap, we conducted this study to estimate the global prevalence of delayed ART initiation and identify social and epidemiological factors related to delayed ART initiation in published observational studies in HIV-infected adults, by a systematic review and meta-analysis.

Materials and methods

Search strategy

We searched three English language electronic databases, PubMed/Medline, Web of Science, and Embase, and three Chinese language Databases, CNKI (China National Knowledge Infrastructure), Wanfang, and Chongqing VIP databases. Our comprehensive search strategies combined terms and variants of HIV (“human immunodeficiency virus”, “acquired immunodeficiency syndrome”), treatment (therapeutics, “antiretroviral therapy, highly active”), and delay (Time-to-Treatment, defer, same-day, early, instant, immediate, rapid, quick) using both controlled vocabularies and free text words. Search queries were optimized to fit the specific feature of each database (S1 File). The electronic database search was supplemented by scanning the reference list of included articles, previous reviews and published meta-analysis. All study steps of this systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (S1 Table) [27].

Inclusion and exclusion criteria

Studies complying with the following inclusion criteria were included: (1) Studies published in English or Chinese between January 2015 and August 2022; (2) HIV-infected adults (≥15Y); (3) Studies reported time to ART initiation (namely, time from diagnosis to ART initiation) and delayed initiation prevalence or gave sufficient information to calculate this estimate. We excluded case reports, study protocols, commentaries, correspondence, letters, reviews or systematic reviews and studies carried out with pregnant women or people with serious, opportunistic infections due to the clinical management of these patients being complex.

Selection of studies

All searched articles from different databases were exported to the Endnote reference manager, and duplicates were removed. Then, two authors (Tao and Xie) independently evaluated the potentially relevant articles by checking the titles and abstracts. Those articles that did not meet the inclusion criteria were removed, and the full texts of the remaining articles were retrieved based on the inclusion and exclusion criteria. Any discrepancies that arose during the selection process were resolved by the adjudicator (Xiao).

Data extraction and quality assessment

The following elements was extracted from included articles, with use of a preconceived data abstraction form: (1) Characteristics of the study: author name, publication year, study year, study design, country, country income and continent; (2) Characteristics of the sample: sample size, age, gender; (3) HIV-related data: CD4 cell count, the time between HIV diagnosis and ART initiation, the number of participants who delayed ART initiation.

We assessed the methodological quality of included studies using the Newcastle–Ottawa Scale [28]. Though this tool, risk of bias was assessed across the domains of selection, comparability and outcome for the risk of bias revision, and high-quality articles were determined when the score of the scale is five and above out of nine scales. Two authors (Tao and Xie) independently assessed study quality, and disagreements were discussed until a consensus was reached.

Statistical analysis

Statistical analysis was performed using Stata 15. The prevalence estimates of delayed initiation of ART and their 95% confidence interval (CI) were calculated and pooled by time elapsed from HIV diagnosis to ART initiation using a random effect analysis model, accounting for the expected between-study significant heterogeneity [29]. Q-tests and I2 statistics were used to assess the level of heterogeneity among studies [30]. The I2 heterogeneity was categorized as follows: low (25–50%), moderate (50–75%) and high (>75%). Subgroup analysis was undertaken to investigate source of between-study heterogeneity, in terms of country, continent, study year, study design, sample size, age group, gender, CD4 cell count. Sensitivity analysis was carried out by serially omitting each study to assess the influence of individual studies on the robustness of the pooled estimate. Furthermore, publication bias was evaluated though visual inspection of the funnel plot and Egger’s tests [31].

Results

Study results and characteristics

The PRISMA flow diagram outlines the search strategy to identify the articles (Fig 1). In total, 34937 publications were identified, of which 34533 were excluded as duplicated or irrelevant according to title and abstract. Full-text assessment was undertaken for leaving 404 potentially articles. After a detailed full-text review, 29 eligible articles [32–60] were included in the analysis.

Fig 1. Flow diagram of the studies included in the meta-analysis on delayed ART treatment.

Fig 1

Open in a new tab

Number of participants ranged from 244 in a Chinese cohort [49] to 34528 in an African cohort [43], and a total of 121142 participants across 15 countries participated in the 29 included studies. More than half of the studies (n = 16) [37, 46–60] were conducted in Asia, followed by Africa (n = 9), Europe (n = 3) [32, 35, 40] and North America (n = 1) [39]. The target population included ART-initiated patients and HIV-positive patients including patients who did not start treatment. One study only provided prevalence in patients aged from 15 to 19 years [46]. Seven studies reported the mean time to initiate ART after HIV confirmation, ranging from five to 40 days [32, 35, 36, 46, 47, 49, 52]. In addition, 18 studies used a cohort [32–37, 39, 41–45, 48–52, 54] design, 10 studies used a cross-sectional design [40, 46, 47, 53, 55–60], and one study [38] used quasi-experimental study. We evaluated the quality of 28 of 29 studies. One meeting abstract cannot be accessed without full text [34]. The quality of 28 studies ranged from three to eight. A detailed description of the characteristics of all enrolled studies is displayed in Table 1.

Table 1. Summary of included studies on prevalence of delayed ART initiation.

Author Year Country Continent Country income Study design Population Age, mean (IQR)(y) Male Mean time to ART initiation (d) Sample size Event Quality score
Lee et al. [32] 2019 UK Europe High income Retrospective cohort HIV-positive ≥18, 37 (31–47) 213 29d (R:0-514d) 292 165 7
Mshweshwe-Pakela et al. [33] 2020 South Africa Africa Lower-middle income Retrospective cohort HIV-positive ≥18, 32 (27–39) 298 NR 826 172 7
Ross et al. [34] 2020 Rwanda Africa Lower-middle income Prospective cohort HIV-positive ≥15 NR NR 1971 458 —a
D’Arminio et al. [35] 2020 Italy Europe High income Prospective cohort ART-initiated ≥18, 38 (29–47) 1038 40d (IQR:21-73d) 1247 783 7
Onoya et al. [36] 2020 South Africa Africa Lower-middle income Prospective cohort HIV-positive ≥18 NR R: 5-8d 883 197 6
Teeraananchai et al. [37] 2020 Thai Asia Upper-middle income Retrospective cohort HIV-positive R: 15–24 22075 NR 29782 14174 8
Lebelonyane et al. [38] 2020 Botswana Africa Upper-middle income Quasi-experimental HIV-positive 33 (26–41) 361 NR 800 122 7
Bacon et al. [39] 2021 USA North America High income Retrospective cohort HIV-positive ≥30 NR R: 6-37d 915 500 7
Kaide et al. [40] 2021 UK Europe High income Cross-sectional HIV-positive ≥16 1704 NR 2281 1182 3
Onoya et al. [41] 2021 South Africa Africa Lower-middle income Prospective cohort HIV-positive ≥18 NR NR 266 95 6
Dah et al. [42] 2021 Cote d’Ivoire, Mali, Togo, Burkina Faso Africa Lower-middle income
low income, low income, low income		 Prospective cohort HIV-positive, MSM 24.0 (21.2–27.7) 350 5d (IQR: 1-13d) 350 52 6
Mody et al. [43] 2021 Zambia Africa Lower-middle income Retrospective cohort HIV-positive ≥18 13116 NR 34528 4489 8
Beesham et al. [44] 2022 Eswatini,Kenya, South Africa, Zambia Africa Upper-middle income, Lower-middle income, Upper-middle income
Lower-middle income,		 Retrospective cohort HIV-positive 16–35 0 NR 304 176 7
MacKellar et al. [45] 2022 Eswatini Africa Upper-middle income Retrospective cohort HIV-positive ≥15 319 306d (IQR: 8d-unknown) 769 505 7
Xu et al. [46] 2019 China Asia Upper-middle income Cross-sectional ART-initiated, sexual transmission R: 15–19 NR 29d (IQR:13-85d) 4990 2462 4
Yu et al. [47] 2019 China Asia Upper-middle income Cross-sectional ART-initiated ≥15 NR 38d (IQR:16-186d) 5191 2348 4
Ma et al. [48] 2019 China Asia Upper-middle income Retrospective cohort HIV-positive, Heterosexual transmission ≥18 NR NR 4409 1157 7
Yuan et al. [49] 2020 China Asia Upper-middle income Retrospective cohort ART-initiated ≥15, 36 (27,46) 213 15d (IQR:11-26d) 244 49 5
He et al. [50] 2020 China Asia Upper-middle income Retrospective cohort ART-initiated ≥18 NR NR 1504 334 7
Zhang et al. [51] 2020 China Asia Upper-middle income Retrospective cohort HIV-positive ≥16, 46.52±16.09 335 NR 406 185 7
Nong et al. [52] 2021 China Asia Upper-middle income Retrospective cohort HIV-positive ≥30 NR R: 11-12d 3976 1377 7
Wu et al. [53] 2021 China Asia Upper-middle income Cross-sectional ART-initiated ≥18 NR 17d 3528 864 6
Yu et al. [54] 2021 China Asia Upper-middle income Retrospective cohort HIV-positive 32.7±11.4 2197 NB 2197 812 7
Feng et al. [55] 2021 China Asia Upper-middle income Cross-sectional ART-initiated ≥15 1819 1.35m (IQR: 0.53–9.55m) 2054 971 7
Zhu et al. [56] 2021 China Asia Upper-middle income Cross-sectional ART-initiated 36.05±12.51 6813 NB 7425 2967 7
Yang et al. [57] 2022 China Asia Upper-middle income Cross-sectional HIV-positive R: 16–92, 54.79±16.56 744 NB 1026 402 6
Tian et al. [58] 2022 China Asia Upper-middle income Cross-sectional ART-initiated ≥18 2568 NB 3859 1258 6
Guo et al. [59] 2022 China Asia Upper-middle income Cross-sectional HIV-positive ≥15 3121 NB 3281 926 6
Yang et al. [60] 2022 China Asia Upper-middle income Cross-sectional HIV-positive R: 30–90 NR NB 1065 416 6
Open in a new tab

Abbreviations: ART = Antiretroviral Therapy; HIV = Human Immunodeficiency Virus; d = days; m = months, NR = Not Report; IQR = Interquartile Range; R = Range

aThe meeting abstract cannot be accessed without full text

Prevalence of delayed initiation of ART

Analyzing the global prevalence of delayed initiation of ART among patients using the random-effects model, we found the pooled prevalence of delayed ART initiation was 36.1% (95% CI: 29.7–42.5%; I2 = 99.8, p<0.001). Fig 2 shows the forest plot of the 29 studies reporting the prevalence of delayed treatment.

Fig 2. Estimated prevalence of delayed ART initiation.

Fig 2

Open in a new tab

NOTE: Weights are from random-effects model.

Subgroup analysis

Subgroup analyses were conducted to compare the prevalence of delayed ART initiation by regions, research design, age, gender, and CD 4 cell count (Table 2).

Table 2. Subgroup analysis of prevalence of delayed ART initiation.

Category Subgroup No of study Prevalence (95% CI) (%) Sample I2 (%) P P (Egger’s test) Between-group difference
Total 29 36.1 (29.7–42.5) 121142 99.8 <0.001 0.027
Continent Asia 16 36.2 (31.4–41.0) 74937 99.4 <0.001 0.056
Africa 9 26.9 (19.4–34.4) 41470 99.2 <0.001 0.013
Europe 3 57.0 (49.1–65.0) 3820 95.1 <0.001 0.778
North America 1 54.6 (51.4–57.9) 915 - - -
p<0.001
Country China 15 39.1 (36.1–42.0) 45155 99.1 <0.001 0.890
Others 14 41.0 (38.7–43.6) 75987 99.9 <0.001 0.209
p = 0.695
Country income High income 4 56.4 (50.8–62.1) 4735 92.7 <0.001 0.709
Upper-middle income 18 35.5 (30.8–40.1) 77297 99.5 <0.001 0.029
Lower-middle income 5 22.7 (16.1–29.3) 38474 98.3 <0.001 0.010
p<0.001
Study design Cohort 18 35.3 (26.2–44.4) 85642 99.9 <0.001 0.153
Cross-sectional 10 39.7 (33.9–45.6) 34700 99.2 <0.001 0.727
Quasi-experimental 1 15.3 (12.8–17.7) 800 - - -
p<0.001
Sample size <1000 10 45.6 (23.8–44.8) 5286 98.8 <0.001 0.092
1000–3000 9 40.4 (31.7–49.1) 14887 99.2 <0.001 0.269
>3000 10 34.1 (22.8–45.5) 100969 99.8 <0.001 0.125
p<0.001
Sex Male 9 39.3 (32.2–46.4) 15109 98.6 <0.001 0.863
Female 8 36.5 (26.9–50.7) 2237 97.2 <0.001 0.257
p = 0.036
Age-specific group (Y) 15–29 6 43.3 (32.6–54.0) 7590 98.4 <0.001 0.629
30–49 4 39.8 (25.1–54.5) 3721 98.8 <0.001 0.432
50- 5 38.4 (33.8–43.0) 4577 98.2 <0.001 0.569
p = 0.041
CD4 cell count (cells/mm 3 ) ≤200 6 25.3 (18.7–31.9) 2410 93.1 <0.001 0.175
201–500 3 33.4 (17.0–49.8) 1864 97.8 <0.001 0.984
>500 3 40.3 (14.0–66.5) 659 98.1 <0.001 0.673
p<0.001
Open in a new tab

Prevalence estimates from studies performed in China (39.1%, 95% CI: 36.1–42.0%) was lower than those performed outside China (41.0%, 95% CI: 38.7–43.6%). The pooled prevalence in high-income countries (56.4%, 95% CI: 50.8–62.1%) was higher than that in upper-middle income countries (35.5%, 95% CI: 30.8–40.1%) and in lower-middle income countries (22.7%. 95% CI: 16.1–29.3%). We further stratified studies by continent. The pooled estimates were highest for studies conducted in Europe. The estimated pooled prevalence among the studies that used cross-sectional design (37.5%, 95% CI: 31.3–43.7%) was higher than those studies that used cohort design (35.3%, 95% CI: 26.2–44.4%). In addition, the pooled prevalence decreased with age. The prevalence was the highest in the 15–29 age group compared to in the 30–49 age group and the lowest in patients aged 50 or over, with pooled prevalence 43.3%, 39.8%, and 38.4%, respectively. When the prevalence was stratified by gender, we found that male population (39.3%, 95% CI: 32.2–46.4%) had a slightly higher prevalence than female population (36.5%, 95% CI: 26.9–50.7%). With the CD4 cell count, the pooled estimates showed an upward trend. Pooled prevalence estimates for patients with CD4 cell count under 200 cells/mm3, between 200-500cells/mm3 and over 500 cells/mm3 was 25.3%, 33.4% and 40.3%, respectively.

Sensitivity analysis

We performed a sensitivity analysis using the random-effects model to identify the effect of individual studies on the overall meta-analysis. No significant changes in the overall pooled prevalence for delated ART initiation were found on the removal of a single study (S1 Fig).

Publication bias

Visual inspection of the funnel plot of studies reporting on the delayed treatment revealed significant asymmetry (Fig 3). The egger’s test showed evidence of significant publish bias (P = 0.027) which further support the finding of the funnel plot.

Fig 3. The funnel plot of studies reporting the prevalence of delayed ART initiation.

Fig 3

Open in a new tab

Discussion

The current study is the first meta-analysis using a comprehensive search strategy to explore the global prevalence of delayed ART initiation among HIV-infected patients. The studies included in this review showed a high prevalence of delayed ART initiation. Our study revealed that the pooled prevalence was 38.0%, lower than the pre-2015 delayed initiation rate ranging from 41%-85% [61–64]. A previous systematic review of six studies conducted in sub-Saharan Africa in 2012 by Mugglin et al. found that the median time of the whole period from HIV diagnosis to ART initiation ranged from a few weeks to more than six months [65]. In our study, the median time from HIV diagnosis to ART initiation varied from five days to 40 days, which is still a gap from the WHO recommendation of starting treatment within seven days or on the same day of confirming HIV diagnosis [66].

Although the WHO guidelines encourage early initiation of ART and HIV treatment has proven to be effective, the decision to start treatment takes into account various factors. It is increasingly recognized that, earlier ART initiation is associated with a low incidence of severe HIV morbidity, disease progression, better immune recovery and longer survival time [67]. Despite this, some patients may opt to delay initiation of ART due to concerns about side effects, pill interaction and financial constraints. This is particularly true for patients who have non-AIDS-defining conditions and serious, opportunistic infections that fall outside the scope of this study [68]. In addition, different countries have recommended ART initiation at varying levels of CD4 count because of medical resources and economic concerns [67, 69].

In this systematic review, we identified studies from 15 countries. Surprisingly, patients in high-income countries delayed treatment at a much higher rate than patients in upper- and lower-middle income countries. This might be explained by the fact that implementing “treat all” is rapidly expanding in upper- and lower-middle income countries, 82 of which have officially adopted the recommendation to provide universal HIV treatment to HIV-infected individuals [6]. In addition, many effective interventions, including simplified ART initiation procedures [8, 70], short message service (SMS) health messages [71], and grassroots prevention and control service model which integrated the resources of the health and medical service network and accelerated HIV treatment services [52], have been implemented in upper- and lower-middle income countries, which accelerated the initiation of treatment. The relationship between national income levels and late treatment initiation needs to be further explored.

Our systematic review found that delayed initiation of ART was more common in male patients than in females, a finding that is in line with the previous study conducted in 6 sub-Saharan African countries showing that men had a significantly higher risk of delaying treatment after enrollment in HIV care than women [72]. Hibbard et al. also reported that females use HIV health services more often than males [73]. However, gender inequalities and gender-based violence persist, increasing women’s blocks access to services. Previous studies revealed a positive association between use of ART among women and sexual and physical partner violence [74, 75]. In 2021, UNAIDS Board adopted the new Global AIDS Strategy 2021–2026, End Inequalities, End AIDS, which propels the process of ending AIDS [76]. Strategies and attention on tackling delayed initiation of ART should thus be focused equally on both genders.

We discovered that patients younger than 30 years of age were more likely to delay initiation of treatment than patients older than 50 (47.3% VS 43.3%), which is consistent with other studies conducted among general HIV-infected patients [77, 78]. A possible reason for the age difference is that since HIV requires lifetime treatment, patients who start treatment at a younger age will get a longer duration of therapy, and long-term medicine would be a serious burden. Financial stress has been identified as a main barrier to initiating and adhering to HIV treatment among young adults [79]. Substantial subsidies for ART drugs, as well as more social benefits for young adults, are expected to increase their affordability, especially in terms of paying out-of-pocket for prescription ART drugs, so that they can rapidly start HIV treatment and achieve higher ART coverage [80].

Our study also found that a higher CD4 cell count was related to the late onset of ART. Although the implementation of the new WHO guidelines on HIV treatment, regardless of CD4 count, was effective for timely initiation of ART, especially for patients who are unavailable to services and have a high probability of delayed or non-initiation of treatment after diagnosis [81, 82], a high CD4 cell count remains a risk factor for timing initiation of treatment. This may be because many asymptomatic HIV-infected patients consider themselves to be healthy in the presence of high CD4 counts. As a result, they thought they could delay treatment until they develop HIV-related symptoms [83]. Previous studies have also confirmed that feeling healthy and the late appearance of HIV-related symptoms are independent factors for the late initiation of ART [84]. ART initiation counseling should highlight the benefit of early treatment and motivate them to participate in the care system. Additional support and other intervention measures to facilitate the care cascade over time were needed for those patients.

Given the current prevalence of delayed ART initiation, effective measures are needed to increase patient awareness of early treatment. Failure to initiate treatment rapidly after diagnosis hinders the effectiveness of ART as a prevention method for HIV mortality and morbidity, suggesting a great need to explore patient concerns about starting treatment and develop strategies to overcome them. Several studies have identified factors associated with delayed ART initiation, including structural and individual-level barriers [23, 85, 86]. The inconvenience of treatment as structural barriers, side effects, stigma, and lack of support as individual-level barriers were the most common concerns about ART initiation. Increased social support from close friends and family has been shown to be effective in facilitating ART initiation [87]. A systematic review suggested that home-based ART services as an alternative to a centralized medical care system were another effective way to deliver ART and increase linkage to care [88].

Despite the robust findings, our study has some limitations. First, some relevant literature may have been missed, since only English or Chinese articles were included, and grey literature was not searched. Additionally, most of data were derived from studies in China and South Africa, and the pooled estimates could not be well representative of the world. Further, some of the studies in our analysis were conducted in patients who initiated ART, and those not receiving treatment were not included in the study, which may lead to an underestimation of the rate of delayed ART initiation. Lastly, the observed heterogeneity was high in the overall analysis. Although subgroup analysis found some factors that affect the result, the extent to which we can explain observed heterogeneity is limited.

Conclusions

Our systematic review revealed a high prevalence of delayed ART initiation. Comprehensive strategies and collaboration between countries and multilateral institutions to accelerate ART initiation have become increasingly critical, and the WHO recommendation supporting rapid initiation should be implemented. The prevalence of delayed treatment was higher in younger patients and those with high CD4 counts, suggesting more effective intervention strategies to promote early treatment should be provided to those high-risk patients.

Supporting information

S1 File. Datail of PubMed database search strategies.

(DOCX)

Click here for additional data file. (12.9KB, docx)
S1 Table. PRISMA 2020 checklist.

(DOCX)

Click here for additional data file. (29KB, docx)
S1 Fig. Sensitivity analysis.

(TIF)

Click here for additional data file. (13.1MB, tif)

Acknowledgments

We thank Professor WILEY Jim, Department of Family and Community Medicine and Institute for Health Policy Studies, University of California, San Francisco (UCSF), for guidance.

Data Availability

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

Funding Statement

The research was funded by Provincial Natural Science Foundation of Hunan Grant (No. 2022JJ30769). The recipient of this fund was corresponding author Honchoing Wang. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.The Joint United Nations Programme on HIV/AIDS (UNAIDS). Global HIV & AIDS statistics—Fact sheet. 2022 [Cited 2023 May 20]. Available from: https://www.unaids.org/en/resources/fact-sheet
  • 2.Granich R, Gupta S, Hersh B, Williams B, Montaner J, Young B, et al. Trends in AIDS deaths, new infections and ART coverage in the top 30 countries with the highest AIDS mortality burden; 1990–2013. PloS One. 2015; 10(7):e131353. doi: 10.1371/journal.pone.0131353 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Tobin SC. U = U gains strength with release of PARTNER2 data. AIDS. 2019; 33(3):N1. doi: 10.1097/QAD.0000000000002098 [DOI] [PubMed] [Google Scholar]
  • 4.Ingabire PM, Semitala F, Kamya MR, Nakanjako D. Delayed antiretroviral therapy (ART) initiation among hospitalized adults in a resource-limited settings: A challenge to the global target of ART for 90% of HIV-infected individuals. AIDS Res Treat. 2019; 2019:1832152. doi: 10.1155/2019/1832152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Tao LL, Liu M, Li SM, Liu J, Jiang SL, Wang LJ, et al. Impact of antiretroviral therapy on the spread of human immunodeficiency virus in Chaoyang district, Beijing, China: using the Asian epidemic model. Chin Med J (Engl). 2017; 130(1):32–8. doi: 10.4103/0366-6999.196571 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Wold Health Organization. HIV/AIDS. 2021 [Cited 2022 September 1]. Available from: https://www.who.int/news-room/fact-sheets/detail/hiv-aids
  • 7.Rosen S, Maskew M, Fox MP, Nyoni C, Mongwenyana C, Malete G, et al. Initiating antiretroviral therapy for HIV at a patient’s first clinic visit: The RapIT randomized controlled trial. PloS Med. 2016; 13(5):e1002015. doi: 10.1371/journal.pmed.1002015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Amanyire G, Semitala FC, Namusobya J, Katuramu R, Kampiire L, Wallenta J, et al. Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial. Lancet HIV. 2016; 3(11):e539–48. doi: 10.1016/S2352-3018(16)30090-X [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011; 365(6):493–505. doi: 10.1056/NEJMoa1105243 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Joseph DD, Kehoe K, Serrao C, Prins M, Mkhize N, Hlophe K, et al. Same-day antiretroviral therapy is associated with increased loss to follow-up in South African public health facilities: a prospective cohort study of patients diagnosed with HIV. J Int AIDS Soc. 2020; 23(6):e25529. doi: 10.1002/jia2.25529 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Kerschberger B, Boulle A, Kuwengwa R, Ciglenecki I, Schomaker M. The impact of same-day antiretroviral therapy initiation under the World Health Organization treat-all policy. Am J Epidemiol. 2021; 190(8):1519–32. doi: 10.1093/aje/kwab032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Ahmed I, Demissie M, Worku A, Gugsa S, Berhane Y. Virologic outcomes of people living with human immunodeficiency virus who started antiretroviral treatment on the same-day of diagnosis in Ethiopia: a multicenter observational study. PloS One. 2021; 16(9):e257059. doi: 10.1371/journal.pone.0257059 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Ouattara EN, MacLean RL, Danel C, Borre ED, Gabillard D, Huang M, et al. Cost-effectiveness and budget impact of immediate antiretroviral therapy initiation for treatment of HIV infection in Côte d’Ivoire: a model-based analysis. PloS One. 2019; 14(6):e219068. doi: 10.1371/journal.pone.0219068 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Boyer S, March L, Kouanfack C, Laborde-Balen G, Marino P, Aghokeng AF, et al. Monitoring of HIV viral load, CD4 cell count, and clinical assessment versus clinical monitoring alone for antiretroviral therapy in low-resource settings (Stratall ANRS 12110/ESTHER): a cost-effectiveness analysis. Lancet Infect Dis. 2013; 13(7):577–86. doi: 10.1016/S1473-3099(13)70073-2 [DOI] [PubMed] [Google Scholar]
  • 15.Njei B, Kongnyuy EJ, Kumar S, Okwen MP, Sankar MJ, Mbuagbaw L. Optimal timing for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis. Cochrane Database Syst Rev. 2013(2):D9012. doi: 10.1002/14651858.CD009012.pub2 [DOI] [PubMed] [Google Scholar]
  • 16.Saag MS, Benson CA, Gandhi RT, Hoy JF, Landovitz RJ, Mugavero MJ, et al. Antiretroviral drugs for treatment and prevention of HIV infection in Adults: 2018 Recommendations of the international antiviral society-USA panel. JAMA. 2018; 320(4):379–96. doi: 10.1001/jama.2018.8431 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Mayanja Y, Kamacooko O, Bagiire D, Namale G, Kaleebu P, Seeley J. ’Test and treat’ among women at high risk for HIV-infection in Kampala, Uganda: antiretroviral therapy initiation and associated factors. AIDS Behav. 2018; 22(3):1053–61. doi: 10.1007/s10461-017-1973-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Wei XQ, He JM, Zheng J, Tan BY Zhang YY, Chen X. Analysis on influential factors of immune restoration in HAART in Hunan province. Practical Preventive Medicine. 2020; 27:1044–7. 10.3969/j.issn.1006-3110.2020.09.006 [DOI] [Google Scholar]
  • 19.Maughan-Brown B, Harrison A, Galárraga O, Kuo C, Smith P, Bekker LG, et al. Factors affecting linkage to HIV care and ART initiation following referral for ART by a mobile health clinic in South Africa: evidence from a multimethod study. J Behav Med. 2019; 42(5):883–97. doi: 10.1007/s10865-018-0005-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Rosen S, Fox MP. Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review. PloS Med. 2011; 8(7):e1001056. doi: 10.1371/journal.pmed.1001056 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Nicolau V, Cortes R, Lopes M, Virgolino A, Santos O, Martins A, et al. HIV infection: time from diagnosis to initiation of antiretroviral therapy in Portugal, a multicentric study. Healthcare (Basel). 2021; 9(7). doi: 10.3390/healthcare9070797 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Plazy M, Newell ML, Orne-Gliemann J, Naidu K, Dabis F, Dray-Spira R. Barriers to antiretroviral treatment initiation in rural KwaZulu-Natal, South Africa. HIV Med. 2015; 16(9):521–32. doi: 10.1111/hiv.12253 [DOI] [PubMed] [Google Scholar]
  • 23.Fatukasi TV, Cole SR, Moore RD, Mathews WC, Edwards JK, Eron JJ. Risk factors for delayed antiretroviral therapy initiation among HIV-seropositive patients. PloS One. 2017; 12(7):e180843. doi: 10.1371/journal.pone.0180843 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Medland NA, Chow E, McMahon JH, Elliott JH, Hoy JF, Fairley CK. Time from HIV diagnosis to commencement of antiretroviral therapy as an indicator to supplement the HIV cascade: dramatic fall from 2011 to 2015. PloS One. 2017; 12(5):e177634. doi: 10.1371/journal.pone.0177634 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Su S, Li S, Li S, Gao L, Cai Y, Fu J, et al. Gaps in the continuum of HIV Care: long pretreatment waiting time between HIV diagnosis and antiretroviral therapy initiation leads to poor treatment adherence and outcomes. Biomed Res Int. 2016; 2648923. doi: 10.1155/2016/2648923 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Rosen S, Maskew M, Larson BA, Brennan AT, Tsikhutsu I, Fox MP, et al. Simplified clinical algorithm for identifying patients eligible for same-day HIV treatment initiation (SLATE): results from an individually randomized trial in South Africa and Kenya. PloS Med. 2019; 16(9):e1002912. doi: 10.1371/journal.pmed.1002912 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021; 10(1):89. doi: 10.1186/s13643-021-01626-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25(9):603–5. doi: 10.1007/s10654-010-9491-z [DOI] [PubMed] [Google Scholar]
  • 29.Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010; 1(2):97–111. doi: 10.1002/jrsm.12 [DOI] [PubMed] [Google Scholar]
  • 30.Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J. Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods. 2006; 11(2):193–206. doi: 10.1037/1082-989X.11.2.193 [DOI] [PubMed] [Google Scholar]
  • 31.Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109):629–34. doi: 10.1136/bmj.315.7109.629 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Lee MJ, Venturelli S, McKenna W, Teh J, Negedu O, Florman KE, et al. Reasons for delayed antiretroviral therapy (ART) initiation in the era of early ART initiation guidelines: a retrospective service evaluation. Int J Std AIDS. 2019; 30(4):415–8. doi: 10.1177/0956462418814985 [DOI] [PubMed] [Google Scholar]
  • 33.Mshweshwe-Pakela N, Hansoti B, Mabuto T, Kerrigan D, Kubeka G, Hahn E, et al. Feasibility of implementing same-day antiretroviral therapy initiation during routine care in Ekurhuleni District, South Africa: Retention and viral load suppression. South Afr J HIV Med. 2020; 21(1):1085. doi: 10.4102/sajhivmed.v21i1.1085 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ross J, Murenzi G, Hoover DR, Shi Q, Kim HY, Muhoza B, et al. Association between time to art and loss to care among newly diagnosed PLWH in Rwanda. Topics in Antiviral Medicine. 2020; 28(1):405. [Google Scholar]
  • 35.D’Arminio MA, Tavelli A, Cozzi-Lepri A, Castagna A, Passerini S, Francisci D, et al. Virological response and retention in care according to time of starting ART in Italy: data from the Icona Foundation Study cohort. J Antimicrob Chemother. 2020; 75(3):681–9. doi: 10.1093/jac/dkz512 [DOI] [PubMed] [Google Scholar]
  • 36.Onoya D, Sineke T, Hendrickson C, Mokhele I, Maskew M, Long LC, et al. Impact of the test and treat policy on delays in antiretroviral therapy initiation among adult HIV positive patients from six clinics in Johannesburg, South Africa: results from a prospective cohort study. BMJ Open. 2020; 10(3):e30228. doi: 10.1136/bmjopen-2019-030228 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Teeraananchai S, Kerr SJ, Khananuraksa P, Ruxrungtham K, Puthanakit T. Rapid antiretroviral initiation among Thai youth living with HIV in the National AIDS programme in the era of treatment at any CD4 cell count: a national registry database study. J Int AIDS Soc. 2020; 23 Suppl 5(Suppl 5):e25574. doi: 10.1002/jia2.25574 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Lebelonyane R, Bachanas P, Block L, Ussery F, Abrams W, Roland M, et al. Rapid antiretroviral therapy initiation in the Botswana Combination Prevention Project: a quasi-experimental before and after study. Lancet HIV. 2020; 7(8):e545–53. doi: 10.1016/S2352-3018(20)30187-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Bacon O, Chin J, Cohen SE, Hessol NA, Sachdev D, Coffey S, et al. Decreased time from Human Immunodeficiency Virus diagnosis to care, antiretroviral therapy initiation, and virologic suppression during the Citywide RAPID initiative in San Francisco. Clin Infect Dis. 2021; 73(1):e122–8. doi: 10.1093/cid/ciaa620 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Kaide E, Curtis H, Freedman A, Croxford S, Burns F, Sabin C, et al. A national audit of the management pathways for new HIV diagnoses. Int J Std AIDS. 2021; 32(8):710–7. doi: 10.1177/0956462420987450 [DOI] [PubMed] [Google Scholar]
  • 41.Onoya D, Hendrickson C, Sineke T, Maskew M, Long L, Bor J, et al. Attrition in HIV care following HIV diagnosis: a comparison of the pre-UTT and UTT eras in South Africa. J Int AIDS Soc. 2021; 24(2):e25652. doi: 10.1002/jia2.25652 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Dah TTE, Yaya I, Mensah E, Coulibaly A, Kouamé JBM, Traoré I, et al. Rapid antiretroviral therapy initiation and its effect on treatment response in MSM in West Africa. AIDS (London, England). 2021; 35(13):2201–10. doi: 10.1097/QAD.0000000000003046 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Mody A, Sikazwe I, Namwase AS, Wa MM, Savory T, Mwila A, et al. Effects of implementing universal and rapid HIV treatment on initiation of antiretroviral therapy and retention in care in Zambia: a natural experiment using regression discontinuity. Lancet HIV. 2021; 8(12):e755–65. doi: 10.1016/S2352-3018(21)00186-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Beesham I, Issema R, Palanee-Phillips T, Onono M, Evans S, Beksinska M, et al. ART initiation among women newly diagnosed with HIV in a contraceptive trial in sub-Saharan Africa. AIDS Care. 2022; 34(4):478–85. doi: 10.1080/09540121.2021.1944601 [DOI] [PubMed] [Google Scholar]
  • 45.MacKellar D, Hlophe T, Ujamaa D, Pals S, Dlamini M, Dube L, et al. Antiretroviral therapy initiation and retention among clients who received peer-delivered linkage case management and standard linkage services, Eswatini, 2016–2020: retrospective comparative cohort study. Arch Public Health. 2022; 80(1). doi: 10.1186/s13690-022-00810-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Xu MJ, Zhao Y, Zhao DC, Ma Y. Immediate antiretroviral therapy and its predictors among HIV-infected adolescents though sexual transmission, 2012 to 2017, China. Chin J of AIDS & STD. 2019; 25(04):346–349. [Google Scholar]
  • 47.Yu L, Hui S, Li T, Tong X, Ma J. Epidemiological characteristics of AIDS patients receiving free antiviral treatment for the first in Heilongjiang, 2004–2018. Chin J of PHM. 2019; 35(03):375–377. [Google Scholar]
  • 48.Ma J, Luo YX, Chen YZ, Dong XQ, Zhao Y. Predicators of HIV diagnosis and immediate treatment among heterosexual transmitted HIV infected patients in two prefectures of Yunnan Province. Chin J of AIDS & STD. 2019; 25(12):1211–1214. [Google Scholar]
  • 49.Yuan XL. Intervention analysis of one-stop AIDS service in Zhuhai City on antiviral treatment of HIV/AIDS patients. Zunyi Medical University, 2020. Available from: https://cdmd.cnki.com.cn/Article/CDMD-10661-1020820126.htm [Google Scholar]
  • 50.He JY, Wang SL, Xu YY, Shen WW, Ding YY, Lin HJ, et al. Influencing factors of antiretroviral therapy and its association with immunological effect among HIV/AIDS patients in Taizhou city, 2006–2019. Chin J of Epidemiol. 2020; 41(12):2093–2097. doi: 10.3760/cma.j.cn112338-20200611-00833 [DOI] [PubMed] [Google Scholar]
  • 51.Zhang X, Luo MN, HE XG, Wang W. Timely initiation of antiretroviral treatment for newly diagnosed HIV /AIDS and tis influencing factors in Quzhou from 2016 to 2018. Chin J of Prev Med. 2020; 21(08):929–933. [Google Scholar]
  • 52.Nong LP, Guo D, He B, Tang HY, Cen P, Lin Q, et al. Analysis on effect of grassroots prevention and control service model of AIDS antiviral treatment in Nanning city. Occup and Health 2021; 37(06):764–771. [Google Scholar]
  • 53.Wu H, Che JF, Xu K, Zhang Xl, Li XT, Jin J, et al. Analysis of influencing factors of delay in HIV antiretroviral treatment in Hangzhou from 2004 to 2020. Prev Med. 2021; 33(12):1246–8. 10.19485/j.cnki.issn2096-5087.2021.12.013 [DOI] [Google Scholar]
  • 54.Yu XC, Dai LL, Dong TL, Wu ZY. The impact of COVID-19 on the initiation of ART in newly reported men infected with HIV through male sex. Chin J of AIDS & STD. 2021; 27(8):813–6. 10.13419/j.cnki.aids.2021.08.05 [DOI] [Google Scholar]
  • 55.Feng YT, Xu YJ, Ma YR, Zhu KK, Chen SY. Epidemiology characteristics among HIV/AIDS patients receiving initial antiretroviral therapy in Hainan, 2005–2019. China Tropical Medicine. 2021; 21(7):681–5. 10.13604/j.cnki.46-1064/r.2021.07.14 [DOI] [Google Scholar]
  • 56.Zhu XY, Huang T, Wang GY, Liao MZ, Huang PX, Zhang N, et al. An analysis of factors associated with timeliness of antiretroviral therapy among HIV / AIDS in Shandong province. Chinese J Exp Clin Virol. 2021; 35(4):361–6. [Google Scholar]
  • 57.Yang WT, Ma W, Tan XL. Influencing factors on the timeliness of antiviral therapy initiation in newly reported HIV/AIDS patients in Beibei District of Chongqing from 2017 to 2020. Parasitoses an Infections Diseases. 2022; 20(02):69–73. [Google Scholar]
  • 58.Tian B, Liu J, Jin YM, Yu Min, He R, Li CX. Characteristics and timely treatment of initial ART patients in Kunming from 2010 to 2020. Chin J of AIDS & STD. 2022; 28(04):472–4. 10.13419/j.cnki.aids.2022.04.20 [DOI] [Google Scholar]
  • 59.Guo Y, Zhao FN, Hou JT, Bai JY. Analyse the timeliness of initiation anti-retroviral treatment among newly diagnosed HIV/AIDS cases in Tianjin, 2016–2020. Chin J of AIDS & STD. 2022; 28(01):78–81. 10.13419/j.cnki.aids.2022.01.17 [DOI] [Google Scholar]
  • 60.Yang J, Zhao SJ, Huang LL, Xu K. Analysis of early antiretroviral therapy among newly reported HIV/AIDS cases in Xuchang city, Henan province from 2017 to 2020. Hnan J Pre Med. 2022; 33(3):193–6. 10.13515/j.cnki.hnjpm.1006-8414.2022.03.007 [DOI] [Google Scholar]
  • 61.Bogdanić N, Bendig L, Lukas D, Zekan Š, Begovac J. Timeliness of antiretroviral therapy initiation in the era before universal treatment. Sci Rep. 2021; 11(1):10508. doi: 10.1038/s41598-021-90043-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Wu Z, Zhao Y, Ge X, Mao Y, Tang Z, Shi CX, et al. Simplified HIV testing and treatment in China: analysis of mortality rates before and after a structural intervention. PloS Med. 2015; 12(9):e1001874. doi: 10.1371/journal.pmed.1001874 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Zhao Y, Wu Z, McGoogan JM, Sha Y, Zhao D, Ma Y, et al. Nationwide cohort study of antiretroviral therapy timing: treatment dropout and virological failure in China, 2011–2015. Clin Infect Dis. 2019; 68(1):43–50. doi: 10.1093/cid/ciy400 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Coulaud PJ, Protopopescu C, Ndiaye K, Baudoin M, Maradan G, Laurent C, et al. Individual and healthcare supply-related barriers to treatment initiation in HIV-positive patients enrolled in the Cameroonian antiretroviral treatment access programme. Health Policy Plan. 2021; 36(2):137–48. doi: 10.1093/heapol/czaa153 [DOI] [PubMed] [Google Scholar]
  • 65.Mugglin C, Estill J, Wandeler G, Bender N, Egger M, Gsponer T, et al. Loss to programme between HIV diagnosis and initiation of antiretroviral therapy in sub-Saharan Africa: systematic review and meta-analysis. Trop Med Int Health. 2012; 17(12):1509–20. doi: 10.1111/j.1365-3156.2012.03089.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.World Health Organization. Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy. 2017. Jan 1 [Cited 2022 September 1]. Available from: https://WWW.who.int/publication/i/item/9789241550062 [PubMed] [Google Scholar]
  • 67.World Health Organization. Guideline on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. 2015. Sep 1 [Cited 2022 September 1]. Available from: https://WWW.who.int/publication/i/item/978924155009565 [PubMed] [Google Scholar]
  • 68.Chelkeba L., Fekadu G., Tesfaye G., Belayneh F., Melaku T., & Mekonnen Z. Effects of time of initiation of antiretroviral therapy in the treatment of patients with HIV/TB co-infection: a systemic review and meta-analysis. Ann Med Surg. 2020; 55, 148–158. doi: 10.1016/j.amsu.2020.05.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. HIV Med. 2012; 13(Suppl 2):1–85. doi: 10.1111/j.1468-1293.2012.01029.x [DOI] [PubMed] [Google Scholar]
  • 70.Fairall LR, Bachmann MO, Louwagie GM, van Vuuren C, Chikobvu P, Steyn D, et al. Effectiveness of antiretroviral treatment in a South African program: a cohort study. Arch Intern Med. 2008; 168(1):86–93. doi: 10.1001/archinternmed.2007.10 [DOI] [PubMed] [Google Scholar]
  • 71.Elul B, Lamb MR, Lahuerta M, Abacassamo F, Ahoua L, Kujawski SA, et al. A combination intervention strategy to improve linkage to and retention in HIV care following diagnosis in Mozambique: a cluster-randomized study. PloS Med. 2017; 14(11):e1002433. doi: 10.1371/journal.pmed.1002433 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Tymejczyk O, Brazier E, Yiannoutsos CT, Vinikoor M, van Lettow M, Nalugoda F, et al. Changes in rapid HIV treatment initiation after national "treat all" policy adoption in 6 sub-Saharan African countries: regression discontinuity analysis. PloS Med. 2019; 16(6):e1002822. doi: 10.1371/journal.pmed.1002822 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Hibbard JH, Pope CR. Gender roles, illness orientation and use of medical services. Soc Sci Med. 1983; 17(3):129–37. doi: 10.1016/0277-9536(83)90246-0 [DOI] [PubMed] [Google Scholar]
  • 74.Kabwama SN, Bukenya J, Matovu J, Gwokyalya V, Makumbi F, Beyeza-Kashesya J, et al. Intimate partner violence among HIV positive women in care—results from a national survey, Uganda 2016. BMC Womens Health. 2019; 19(1):130. doi: 10.1186/s12905-019-0831-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Closson K, McLinden T, Parry R, Lee M, Gibbs A, Kibel M, et al. Severe intimate partner violence is associated with all-cause mortality among women living with HIV. AIDS. 2020; 34(10):1549–58. doi: 10.1097/QAD.0000000000002581 [DOI] [PubMed] [Google Scholar]
  • 76.The Joint United Nations Programme on HIV/AIDS (UNAIDS). UNAIDS Board adopts new global AIDS strategy which paves the way to end AIDS by 2030. 2021 [Cited 2022 September 1]. Available from:. https://www.unaids.org/en/Global-AIDS-Strategy-2021-2026
  • 77.Govindasamy D, Ford N, Kranzer K. Risk factors, barriers and facilitators for linkage to antiretroviral therapy care: a systematic review. AIDS. 2012; 26(16):2059–67. doi: 10.1097/QAD.0b013e3283578b9b [DOI] [PubMed] [Google Scholar]
  • 78.Lamb MR, Fayorsey R, Nuwagaba-Biribonwoha H, Viola V, Mutabazi V, Alwar T, et al. High attrition before and after ART initiation among youth (15–24 years of age) enrolled in HIV care. AIDS. 2014; 28(4):559–68. doi: 10.1097/QAD.0000000000000054 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.McAllister J, Beardsworth G, Lavie E, MacRae K, Carr A. Financial stress is associated with reduced treatment adherence in HIV-infected adults in a resource-rich setting. HIV Med. 2013; 14(2):120–4. doi: 10.1111/j.1468-1293.2012.01034.x [DOI] [PubMed] [Google Scholar]
  • 80.Mao L, de Wit JB, Kippax SC, Prestage G, Holt M. Younger age, recent HIV diagnosis, no welfare support and no annual sexually transmissible infection screening are associated with nonuse of antiretroviral therapy among HIV-positive gay men in Australia. HIV Med. 2015; 16(1):32–7. doi: 10.1111/hiv.12169 [DOI] [PubMed] [Google Scholar]
  • 81.Boyd MA, Boffito M, Castagna A, Estrada V. Rapid initiation of antiretroviral therapy at HIV diagnosis: definition, process, knowledge gaps. HIV Med. 2019; 20 Suppl 1:3–11. doi: 10.1111/hiv.12708 [DOI] [PubMed] [Google Scholar]
  • 82.Reynolds LJ, Camlin CS, Ware NC, Seeley J. Exploring critical questions for the implementation of "universal test and treat" approaches to HIV prevention and care. AIDS Care. 2016; 28 Suppl 3:1–6. doi: 10.1080/09540121.2016.1178960 [DOI] [PubMed] [Google Scholar]
  • 83.Takah NF, Awungafac G, Aminde LN, Ali I, Ndasi J, Njukeng P. Delayed entry into HIV care after diagnosis in two specialized care and treatment centres in Cameroon: the influence of CD4 count and WHO staging. BMC Public Health. 2016; 16:529. doi: 10.1186/s12889-016-3258-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Jenness SM, Myers JE, Neaigus A, Lulek J, Navejas M, Raj-Singh S. Delayed entry into HIV medical care after HIV diagnosis: risk factors and research methods. AIDS Care. 2012; 24(10):1240–8. doi: 10.1080/09540121.2012.656569 [DOI] [PubMed] [Google Scholar]
  • 85.Sprague C, Simon SE. Understanding HIV care delays in the US South and the role of the social-level in HIV care engagement/retention: a qualitative study. Int J Equity Health. 2014; 13:28. doi: 10.1186/1475-9276-13-28 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Moges NA, Adesina OA, Okunlola MA, Berhane Y. Barriers and facilitators of same-day antiretroviral therapy initiation among people newly diagnosed with HIV in Ethiopia: qualitative study using the transtheoretical model of behavioral change. J Multidiscip Healthc. 2020; 13:1801–1815. doi: 10.2147/JMDH.S282116 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Kelly J, Amirkhanian Y, Yakovlev A, Musatov V, Meylakhs A, Kuznetsova A, et al. Stigma reduces and social support increases engagement in medical care among persons with HIV infection in St. Petersburg, Russia. J Int AIDS Soc. 2014; 17(4 Suppl 3):19618. doi: 10.7448/IAS.17.4.19618 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Ruzagira E, Baisley K, Kamali A, Biraro S, Grosskurth H. Linkage to HIV care after home-based HIV counselling and testing in sub-Saharan Africa: a systematic review. Trop Med Int Health. 2017; 22(7):807–21. doi: 10.1111/tmi.12888 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Chuanyi Ning

19 Dec 2022

PONE-D-22-26544Prevalence of delayed antiretroviral therapy initiation among people living with HIV: a systematic review and meta-analysisPLOS ONE

Dear Dr. Wang,

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 Feb 02 2023 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Chuanyi Ning, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

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

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

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

[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?

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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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)

Reviewer #1: Please consider the following comments:

1. The manuscript should be proofread carefully.

2. Line 15: Please delete the working definition for delayed antiretroviral therapy

3. Line 21: Please provide both names of the database and platform (e.g. Pubmed/Medline)

4. Line 23: Why the authors used both approaches for detecting heterogeneity?

5. Line 24: Meta-regression is not an approach for identifying potential sources of heterogeneity

6. Line 29-30 It seems the sex disparity does not reach the significant difference

7. Line 31-32: How about the results of CD4 level in meta-regression? Please also provide the CI for the results.

8. The content of the introduction is a bit biased. Initiation of ART in the setting of an acute, AIDS-associated opportunistic infection does not follow the "the earlier the better" rule. For some opportunistic infections, such as cryptococcal and TB meningitis, immediate ART initiation may increase the risk of serious Concerns regarding immune reconstitution inflammatory syndrome. A short delay before initiating ART may be warranted. For patients with mild to moderate cutaneous Kaposi sarcoma, initiation of ART can not be done with chemotherapy. Drug interactions should be considered when starting ART.

9. Therefore, pooling the numbers of delayed ART initiation may not guide the clinical practice. The justification for the significance of this review is not clear enough.

10. Line 100 The term "systematic review" and "meta-analysis" are used interchangeably.

11. Line 100 Do You mean non-randomized studies? why does this review exclude randomized studies?

12. Line 101 why does this review include minors?

13. Line 129-133 Please provide the statistical details of meta-regression and sensitivity analysis.

14. Figure 1 The authors stated this review complies with PRISMA 2020. However, the PRISMA Flowchart did not fit the updated PRISMA.

15. Table 1 Please provide only the surname of the first authors.

16. Table 1 Please provide the details of participants' characteristics including mean/median age, age range, sex, study setting, etc.

17. Table 1 Ross J et al Please provide the reasons in the footnote why this study did not report the quality score

18. Table 2 P for the difference in subgroups is needed

19. Table 2 What do you mean by male and female subgroups? only including male/female? or the majority proportion?

20. Table 2 mean age or median age? Do included studies report median age?

21. Table 2 mean CD4 or median CD4?

22. Table 3 It seems the authors misunderstand the difference between meta-regression and subgroup analysis. Year of publication, continent, country, country income, study design, sample size, and quality score could not be the covariates of prevalence of delayed ART initiation. Meta-regression usually included individual-level variables in regression models in each study.

23. Result what are the confounding factors set in the NOS?

24. Did the authors search grey literature?

25. Discussion: As I mentioned above, the delayed use of antiretroviral agents highly relies on the type of OI. This info should be mentioned in the discussion. Considerations when initiating ART are complicated.

26. The heterogeneity was high in all models. It should be listed as a limitation

Reviewer #2: General Comment:

This manuscript reported a systematic review studying the prevalence of delayed treatment (ART) to AIDS and its relevant factors. Overall, this paper contributed important knowledge to the literature. To improve the quality of the manuscript, I listed some suggestions below.

Major Comments:

1. Line 100. “No-randomized” is confusing. Did the study only include non-randomized studies?

2. Line 101. Why did the authors only include studies published between January 2015 and August 2022?

3. Line 103-105. I suggest that the authors provide the reason(s) of excluding studies conducted among pregnant women.

4. Line 108-109. The two authors’ (Tao and Xie) reviewing process was not clearly described. For example, what were the “remaining relevant articles”?

5. The clarity of the process of screening titles and abstracts needs to be improved. For example, in Figure 1. “Record screened by title and abstract” appeared twice.

6. Line 153. I suggest that the authors explain the quality scores. For instance, what does the score of 3 mean?

7. The resolution of figure 2 needs to be increased. The current version is difficult to read.

8. The line 22 on page 17. The first rationale mentioned in the sentence – “the possible reason for the age difference is…for longer” – is difficult to understand. Also, the second rationale – “In addition, they usually…for young HIV-infected people” – is not convincing and needs to be rephrased.

9. The line 9-10 on page 19. The second limitation was difficult to understand. Its clarity needs to be improved.

Minor Comments:

1. Line 55. Please name the countries where the observational studies were conducted.

2. Line 73. There is a grammar error. “Such time from…” needs to be revised to “such as time from…”

3. The manuscript will be strengthened, if the transition between the 3rd and 4th paragraphs could be improved.

4. Line 83. The sentence “…global prevalence of delayed initiation for the time from diagnosis to ART initiation…” is difficult to understand. I suggest rephrasing this sentence.

5. Line 145. I suggest deleting the word “subjects”.

6. In the section of subgroup analysis, the authors mentioned “high-income countries”, “upper-middle income countries”, and “lower-middle income countries”. I suggest adding a column in Table 1 to show the category of each country.

7. Page 17. Some interventions mentioned in the discussion section were not clear. For example, what specific interventions were taken to streamline initiation of ART? What was the specific content of the “grassroots prevention and control service model”?

8. In the section of acknowledgements, the authors state that they thank all colleagues working in Xiangya Nursing School. This section will make more sense if the authors could briefly provide 1 or 2 reasons to illustrate why all colleagues need to be acknowledged.

**********

6. 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: No

Reviewer #2: Yes: Zhao Ni

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Oct 24;18(10):e0286476. doi: 10.1371/journal.pone.0286476.r002

Author response to Decision Letter 0

2 Feb 2023

Dear Editor and Reviewers

Thank you for reviewing our manuscript PONE-D-22-26544 “Prevalence of delayed antiretroviral therapy initiation among people living with HIV: a systematic review and meta-analysis”. We found the comments very helpful in improving our manuscript. In the document "response to reviewers", we list the reviewer comments and our responses. We had presented the updated changes in “italic”.

Again, thank you Editor and reviewers. We are grateful for your consideration and for the potential opportunity to publish this paper in PLOS ONE.

Attachment

Submitted filename: Response to reviwers.docx

Click here for additional data file. (23KB, docx)

Decision Letter 1

Lara Vojnov

17 May 2023

Prevalence of delayed antiretroviral therapy initiation among people living with HIV: a systematic review and meta-analysis

PONE-D-22-26544R1

Dear Dr. Wang,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Lara Vojnov

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

**********

2. 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: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

4. 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

**********

5. 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

**********

6. 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: I am satisfied with the revisions made to the manuscript. Thank you for your diligent efforts in addressing the concerns and improving the overall quality of the document.

Reviewer #2: The authors addressed my comments. There are still some grammatical errors in the manuscript. For example, "clinical management of these patients beingcomplex." should be revised to "clinical management of these patients is complex."

**********

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: No

Reviewer #2: No

**********

Acceptance letter

Lara Vojnov

23 May 2023

PONE-D-22-26544R1

Prevalence of delayed antiretroviral therapy initiation among people living with HIV: a systematic review and meta-analysis

Dear Dr. Wang:

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

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 plosone@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. Lara Vojnov

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 File. Datail of PubMed database search strategies.

    (DOCX)

    Click here for additional data file. (12.9KB, docx)
    S1 Table. PRISMA 2020 checklist.

    (DOCX)

    Click here for additional data file. (29KB, docx)
    S1 Fig. Sensitivity analysis.

    (TIF)

    Click here for additional data file. (13.1MB, tif)
    Attachment

    Submitted filename: Response to reviwers.docx

    Click here for additional data file. (23KB, docx)

    Data Availability Statement

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

    Articles from PLOS ONE are provided here courtesy of PLOS

    RESOURCES