Risk of infections among persons treated with opioids for chronic pain: a systematic review and meta-analysis protocol
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* Irina Kudrina
* M Gaberielle Page
* Manon Choinière
* Yoram Shir
* Mark J Eisenberg
* Maayan Ben-Sasson
* Bertrand Lebouché
* Svetlana Puzhko

## Abstract

**Introduction** Millions of persons with chronic pain across North America and Europe use opioids. While the immunosuppressive properties of opioids are associated with risks of infections, these outcomes could be mitigated through careful patient selection and monitoring practices when appropriate. It is important to recognise that some patients do benefit from a carefully tailored opioid therapy. Enough primary studies have been published to date regarding the role of opioids in potential immunosuppression presenting as an increased rate of infection acquisition, infectious complications and mortality. There is thus a critical need for a consensus in this area.

**Methods and analysis** The methodology is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies and the Cochrane Handbook for Systematic Reviews of Interventions. We plan to systematically search Ovid MEDLINE, CINAHL, PsycINFO, EMB Review, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and Google Scholar databases from their inception date to December 2023. Full-text primary studies that report measurable outcomes in adults with chronic pain, all routes of opioid use, all types of infections and all settings will be included. We will identify a scope of reported infections and the evidence on the association of opioid use (including specific opioid, dosage, formulation and duration of use) with the risk of negative infectious outcomes. Opioid use-associated outcomes, comparing opioid use with another opioid or a non-opioid medication, will be reported. The meta-analysis will incorporate individual risk factors. If data are insufficient, the results will be synthesised narratively. Publication bias and confounding evaluation will be performed. The Grading of Recommendations Assessment, Development and Evaluation framework will be used.

**Ethics and dissemination** Approval for the use of published data is not required. The results will be published, presented at conferences and discussed in deliberative dialogue groups.

**PROSPERO registration number** CRD42023402812.

*   Infectious diseases
*   Immunology
*   Pain management
*   Meta-Analysis
*   Systematic Review

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   This extensive comprehensive systematic review is the first of its kind on the topic.

*   The review will include all types of opioids, doses and routes of administration (except illicit self-injection).

*   Multidatabase and multilingual systematic search will be performed.

*   The review is limited to quantitative studies reporting measurable outcomes only.

*   Not searching for specific infectious agents might result in some pertinent studies being missed.

## Introduction

The COVID-19 pandemic brought to light synergistic public health crises of poorly managed chronic pain (CP)1 and rising opioid prescribing rates,2 3 culminating in increased prevalence of opioid use-associated complications such as acute overdoses or chronic hormonal and immune disturbances.4–6 CP, defined as pain lasting more than 3 months,7 is common worldwide, affecting 18% of the population across developing nations8 and more than 20% of the population in the USA and Canada.9 About 11% of young adults10 and up to 85% of elderly patients11 live with CP, including pain-related disability12 13 frequently associated with opioid use. Reportedly, the direct and indirect costs to society of pain and opioid crises prepandemic ranged anywhere from $38.3 billion to $40.4 billion annually in Canada.14 

The prevalence of opioid use in Canada is estimated at more than 12% of the population,15 making it one of the leading opioid consumers in the world (988 mg morphine equivalent per 1000 inhabitants/day), with similar trends observed across the USA and in European countries such as Germany16 and the Netherlands.17 With age, the proportion of patients with CP using licit and illicit opioids increases,18 and so does the prevalence of opioid-related fatal and non-fatal adverse effects. In 2022 alone, the Canadian government reported ~20 opioid-related deaths and hundreds of hospitalisations daily.19 These statistics, however, do not include a much higher prevalence of opioid use-associated long-term sequela.

Multimorbidity20 and low socioeconomic status are associated with CP21 and opioid use, confounding the development of immunosuppression and poor health22 23 (figure 1). CP disproportionately affects persons from marginalised (racialised, poor, etc) communities and the elderly.11 24 As the WHO pointed out, ‘… health and illness follow a social gradient: the lower the socioeconomic position, the worse the health’.25 Furthermore, an overall link between multimorbidity, polypharmacy, neuroimmune disturbances and infections appears well established.26 Several common chronic disease states, such as metabolic syndrome, inflammatory arthritis, major depression, various pain syndromes, prolonged stress and post-traumatic stress disorder,27–29 are associated with long-term disturbances of the hypothalamic–pituitary–adrenal (HPA) axis, proinflammatory (eg, cytokine-driven) systemic changes27 28 and various degrees of immunosuppression. Unsurprisingly, the risk of negative infectious outcomes in these persons is reportedly higher than in the general population.30–34 Thus, the use of immunosuppressive analgesics like opioids becomes a careful balancing act against their potential capacity to further suppress HPA–immune axes and provide meaningful analgesia.

![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/14/10/e083791/F1.medium.gif)

[Figure 1](http://bmjopen.bmj.com/content/14/10/e083791/F1)

Figure 1 
Direct acyclic graph on the association between opioid use and infectious complications among patients with chronic pain. SES, socioeconomic status.

Our knowledge of opioid-associated infections is not new.35–38 It is important to distinguish between infections resulting from unsterile injection practices, such as those leading to bloodborne infections like HIV, osteomyelitis, skin and epidural abscesses and infective endocarditis,38–41 and infections resulting from the immunosuppressive effects of opioids, which impact immune-related receptors in the human body and affect innate and adaptive immune system responses. Recent reviews42 43 of preclinical and clinical evidence postulate that the most plausible mechanism of immunosuppression by opioids would involve mu-opioid receptors expressed by mammalian tissues. In addition, opioids affect the intestinal microbiome, permeability and bacterial dissemination, as well as the modulation of the central nervous system–HPA axis. Together, these lead to a plethora of closely intertwined effects involving suppression of immune cell proliferation, reduction in antibacterial activity, migration and antigen presentation by the innate immune system (macrophages, neutrophils, dendritic, natural killer (NK) and mast cell activation) and several changes in adaptive immunity (T and B cells).

In the USA (2002–2012), hospitalisations related to opioids and opioid-associated infections cost American Medicaid $15 billion and $700 million, respectively.38 In the province of Ontario (Canada), a significant increase in the rates of infective endocarditis (167%), spinal infections (394%) and skin and soft tissue infections (147%) was also reported (2013–2019). The 10 highest burden pathogens of interest (*Streptococcus pneumoniae*, *Escherichia coli*, human papillomavirus, hepatitis B virus, HIV, hepatitis C virus, *Staphylococcus aureus*, influenza virus, *Clostridium difficile* and rhinovirus) have accounted for >65% of health-adjusted life years lost due to premature morbidity and mortality.44 It is estimated that only antimicrobial-resistant45 and hospital-acquired46 infections cost Canadians an additional $3.5 billion a year.

The importance of the confluent effect of opioid-induced immunosuppression and the risk of infections is difficult to overestimate. There is an already good understanding47 48 of the effectiveness of the HIV and hepatitis C infection prevention strategies in persons who inject illicit opioids. Although the Centers for Disease Control and Prevention (CDC),12 49 Canadian50 and European51 52 opioid prescribing guidelines acknowledge the possibility of endocrine and immune disturbances, they do not offer any guidance on balancing opioid use and risk of infections in populations living with CP. In the field of pain, no consensus has been reached regarding the risk of specific opioids and no corresponding prevention strategies have been identified.

Opioid use for CP presents a spectrum ranging from a subgroup of patients taking occasional small doses of opioids to patients treated with regular medium-dose to high-dose opioid therapy, and all the way to another subgroup of patients who live with concomitant CP and opioid use disorder. It is estimated that >20% of patients with musculoskeletal CP overconsume or misuse opioids and about 15% live with opioid use disorder.53 Similarly, in a systematic review (SR) of 15 studies54 looking at cancer-related CP, opioid misuse was reported to be as high as 27.8% and opioid use disorder ranged up to 20%. The data thus converge to demonstrate that, although most patients with CP do not engage in risky behaviours, therapeutic and recreational uses might not always be easily separable. Many patients diagnosed with opioid misuse or use disorders had their first exposure to an opioid in the context of CP diagnoses.55–57 More so, persistent opioid use could also develop postacute trauma and surgery,58 leading to chronic opioid toxicity and its sequela.

Opioids belong to a diverse class of molecules, including natural ones such as opium, morphine and codeine, and their derivatives (eg, heroin, hydromorphone and oxycodone), and synthetic ones (buprenorphine, tramadol, fentanyl, etc). They exert therapeutic and non-therapeutic effects via the opioid receptors of the endogenous opioid system,4 59 one of the most omnipresent neurotransmitter systems in the mammalian organism closely involved in analgesia, stress and immune responses.4–6 27 60 It has been shown that the mu-opioid receptors are found on immune cells such as macrophages,61 T and B lymphocytes,62 63 natural killer cells64 and even glial cells65 that provide support and protection to the neurons. Notably, opioid-induced glial changes are thought to be implicated in the development of opioid-induced hyperalgesia (abnormally increased pain),66 a phenomenon that can drive prolonged opioid use and dose escalation. Aside from the dose and duration, immunosuppressive effects and risk of infections likely vary by specific opioid.6 67 

Clinical immunosuppression in acute postoperative settings (eg, abdominal surgeries) was also reported. For example, the use of remifentanil anaesthesia is associated with higher infection rates at the surgical sites when compared with fentanyl.68 On the other hand, buprenorphine appears to be one of the safer options,69 70 and long-acting opioid formulations are associated with a greater HPA axis suppression71 72 and a higher risk of infectious complications73 74 than short-acting opioids. Thus, some authors categorise opioids into ‘more immunosuppressive’ (eg, morphine, fentanyl, codeine, dihydrocodeine and methadone) and ‘less immunosuppressive’ (oxycodone, tramadol, buprenorphine and hydromorphone),75–80 although this classification lacks systematic evidence support and is not widely accepted.

### Preliminary data in CP

Despite variations in methodological approaches,81 the trends across primary studies have been pointing to the same direction. A non-systematic biophysiological review23 laid much support to the hypothesis that opioids in general, and especially long-term opioid therapy (>3 months), can alter the parameters of the innate and adaptive immunity in patients with CP in a clinically meaningful way. A preliminary search (15 August 2023) of the Ovid MEDLINE and Google Scholar databases in English revealed a sample of primary and synthesis studies on the topic,1 23 73 74 81–99 analysing the association with serious infections (pneumonia, bacteraemia, sepsis, meningitis*/*encephalitis, septic arthritis*/*osteomyelitis, endocarditis, pyelonephritis and cellulitis) and the corresponding rates of hospitalisations, intensive care unit (ICU) admissions and mortality. The current public health crisis is primarily related to illicit fentanyl and associated analogues, rather than prescription opioids. However, as the prevalence of licit (prescribed and over-the-counter pharmaceuticals) and illicit (not prescribed, pharmaceutical and non-pharmaceutical) opioid use remains a serious concern, and given that sufficient literature has been published to date on the topic, there is a critical need for systematically synthesised knowledge on the risk of opioid use-associated infections in persons with CP, outside of the illicit self-injecting practices. To our knowledge, this SR will be the first on the topic. It will contribute to informing clinical practice guidelines, opioid prescribing policies and clinical practices across Canada and internationally.

### Registration

The protocol was registered in PROSPERO on 18 March 2023 (CRD42023402812).

### Review questions and objectives

#### Review questions

The overarching review question for this SR is: what is the evidence on the association of opioid use with increased risk of infections, reinfections and negative infectious outcomes among persons with CP using opioids (excluding illicit self-injecting practices)?

The secondary review question is: does the association between use of opioids and risk of infectious outcomes depend on the specific opioid, dosage, formulation and duration of use?

#### Objectives

The following are the primary objectives:

1.  Identify the scope of *infections in opioid users (IOU*) as described in studies selected for this SR.

2.  Synthesise the evidence on the difference in infection acquisition risks between persons with CP who use opioids and a comparator as available in the literature.

3.  Synthesise the evidence on the difference in *IOU*-related outcomes (ie, hospitalisations, duration of hospital stays, ICU admissions, mortality, etc) between persons with CP who use opioids and a comparator.

The following are the secondary objectives (data permitting):

1.  Examine if the risk of negative *IOU*-related outcomes is associated with opioid dose, opioid formulation (long-acting vs short-acting) and duration of use.

2.  Identify opioids associated with a higher risk of infection acquisition and/or negative *IOU*-related outcomes.

3.  Identify specific individual-level characteristics that may be associated with an increased risk of infection acquisition and/or negative *IOU*-related outcomes.

## Methods and analysis

The SR methodology is based on the MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies100 and the *Cochrane Handbook for Systematic Reviews of Interventions*.101 The results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.102 This protocol was registered in PROSPERO and important protocol amendments will also be documented in PROSPERO.

### Operational definitions

1.  *CP* includes cancer pain, cancer treatment-induced pain and non-cancer pain.7 103 

2.  *Opioids* are natural compounds, semisynthetic or synthetic molecules exerting their main physiological effects via opioid receptors (mu, delta, kappa). All opioids and their formulations mentioned in the identified primary studies will be included in this SR. For specific opioid names in the search strategy, please refer to table 1.

3.  *IOUs* include all (bacterial, viral and fungal) infections described in studies selected for this SR.

4.  All *routes of administration* (oral, transdermal, intravenous, intrathecal, etc) will be included. Due to the potential risk of shared needle/syringe contamination unrelated to the immunosuppressive properties of studied medicines, we will *exclude* illicit self-injections of opioids.

5.  Various o*pioid use durations* will be considered: acute (1–7 days), short-term (8–30 days), medium-term (>30–120 days) and chronic (>120 days).

6.  *Type of opioid use* will be categorised as episodic (non-daily or 1–6 days a week) or continuous (daily or 7 days a week).

7.  *Outcomes* include infection acquisition rates, infection-related hospitalisations, duration of hospital stays, ICU admissions and mortality.

8.  Regarding *dose reporting*, all reported doses will be recalculated in morphine equivalent daily dose based on the Utah University conversion table,12 104 whenever data permit. For any studies reporting on opioids for which conversion values are not available, a narrative summary will be generated.

View this table:
[Table 1](http://bmjopen.bmj.com/content/14/10/e083791/T1)

Table 1 
PubMed search strategy example

### Eligibility criteria

Eligibility criteria will be defined based on the PECO approach. *Participants* are patients with CP who use opioids (with or without opioid dependence and/or opioid use disorder) and who do not self-inject illegal/recreational opioids. *Exposure* is all opioid use, except illegal self-injection of opioids and kratom plant. *Comparator* is a population from the same setting (eg, ICU) using another opioid or a non-opioid medication. *Outcome* is the scope of the *IOU* and measurable infection-related outcomes (see Outcome reporting section).105 

We will include all relevant primary studies reporting all routes of opioid use by adult humans, all infections (including COVID-19) during opioid use period and all settings. We will include full texts in any language (translated with DeepL ([https://www.deepl.com/en/app](https://www.deepl.com/en/app) 106) or Google Translate) reporting measurable outcomes and various designs (randomised and non-randomised trials, observational studies, case series and mixed methods studies (quantitative portion)). Studies focusing on paediatric populations, palliative/end-of-life care, self-injection of illegal/recreational opioids, qualitative designs, opinions, commentary, abstracts and conference proceedings will be excluded.

### Search strategy

#### Databases

An experienced medical liaison McGill librarian will be involved. We plan to systematically search Ovid MEDLINE, CINAHL, PsycINFO, EMB Review, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and Google Scholar databases from their inception date to December 2023 using a combination of medical subject headings (MeSH) and keywords.

#### Grey literature

ProQuest, dissertation and theses, and published reports will be searched. Keywords and MeSH terms will be entered for the concepts, such as “opioids,” “infections” and “pain,” using Boolean operator AND for (1) all commonly used opioids (generic, brand names and synonyms), (2) infections (all viral, bacterial and other infections) and (3) pain (cancer and non-cancer). The search strategy will be adapted to each database (see example in table 1). Backward and forward citation searches will be performed.

### Study selection

The Covidence systematic review software107 will be used to perform screening, quality assessment and data extraction, and to document decisions on inclusion/exclusion. First, two independent reviewers will screen the manuscripts by titles and abstracts. We will calculate kappa statistics (inter-rater agreement) to ensure consistency of the selection process.108 109 Before screening, a stepwise calibration test will be performed on a sample of 30 studies, with the aim of achieving 80% agreement between reviewers. We will report changes to the inclusion and exclusion criteria that result from the calibration as deviations from the published protocol. All potentially relevant studies will be carried forward at each step. The remaining full texts will be reviewed for eligibility independently by two researchers. Disagreements will be resolved by consensus with a third reviewer.

### Data extraction

To extract the data, we will adopt a modified Effective Practice and Organisation of Care Cochrane data collection forms.101 110 The extracted data will be categorised into (1) patient characteristics (sex at birth, gender, age, sociodemographic, psychosocial and available medical characteristics, such as immunosuppression and number of comorbidities); (2) opioid use status (continuous, episodic or no use, opioid formulation, opioid type and dose); (3) infection-related factors, such as infection diagnosis (eg, pneumonia), infection type (bacterial, viral and fungal) and if available specific infectious agent (eg, *Clostridium*); (4) clinical settings (eg, community, hospital and ICU); (5) clinical disciplines (eg, orthopaedic surgery); and (6) measurable outcomes (eg, duration of hospital stay and ICU admission) and severity (requiring intubation, mechanical ventilation, sepsis, septic shock and mortality). One researcher will extract the data and another researcher will check the extracted data for errors and plausibility.

### Outcome reporting

For primary objective 1, all infections reported in quantitative studies will be documented, and relevant details on the population, settings and opioid use will be described. For primary objective 2, we will synthesise the evidence on the differences in infection acquisition risks between persons who use opioids and a comparator. For primary objective 3, we will synthesise the evidence on the differences in *IOU*-related measurable outcomes (eg, duration of hospital stay) and severity (eg, septic shock) between persons who use opioids and a comparator. For primary objectives 2 and 3, a meta-analysis of the extracted effect measures will be performed; pooled effect measures will be reported (if feasible).

For secondary objective 1, if data allow, we will synthesise the evidence on the relationships between opioid dose, duration of use, opioid formulation (long-acting vs short-acting) and reported *IOU* outcomes. ‘Opioid-naïve’ period prior to exposure, when reported by the primary studies, will be recorded. For secondary objective 2, if data allow, we will identify specific opioids that are associated with a higher risk of infection acquisition and poor outcomes. If data allow, for secondary objective 3, we will identify individual risk factors (eg, age, gender, ethnicity, comorbidities) that are associated with a higher risk of infection acquisition and poor outcomes. Tabulated data and qualitative descriptions will be provided for secondary objectives 1, 2 and 3. Studies on chronic cancer pain and non-cancer pain will be reported separately as well as pooled.

### Risk of bias in individual studies

We will review the included articles and assess the risk of bias for each outcome of interest. Disagreements will be discussed until a consensus is reached. In case of unresolved disagreement, a third reviewer will be invited to appraise the study. We will employ a validated EPHPP (Canadian Effective Public Healthcare Panacea Project) Quality Assessment Tool,111 based on eight categories universally applicable to quantitative studies, which has a good inter-rater and intrarater reliability.112 113 The EPHPP tool is widely cited and was chosen for its excellent properties in evaluating studies in the pain field.113 We will record the study’s funding sources and authors’ conflicts of interest statements.

### Data synthesis

The PRISMA flow chart114 115 will be used to describe the study selection process. We will tabulate the data on the included studies and their populations, the identified risk factors and the outcome characteristics using frequency counts. All measurable outcomes extracted from the included studies will be used in the data synthesis. If two or more studies for a specific measurable outcome are available, we will perform a meta-analysis using the Review Manager (RevMan) software.116 Standardised mean difference with 95% CI for continuous outcomes and ORs, relative risk ratios or HR with 95% CI for dichotomous outcomes will be used in the meta-analysis. Whenever possible, we will transform other effect estimates into these effect measures. Higgins’ I2 statistics101 117 (ie, the percentage of variability in the effect size estimates due to heterogeneity) will be calculated. The I2 statistic is a relative measure of heterogeneity and will be assessed in conjunction with prediction intervals. According to Cochrane recommendations, an I2 statistic of 30%–60% and 50%–90% may, respectively, represent moderate and substantial heterogeneity. Heterogeneity above 75% would be defined as considerable.118 Prediction intervals, which are easier to interpret and relate to clinical implications, estimate a prespecified (95% CI) range of treatment effects expected in future settings.119 120 If the range of treatment effects shown by prediction intervals includes both positive and negative clinically relevant effects, the results of the meta-analysis will be considered inconclusive. Based on our pilot search, we anticipate some data heterogeneity, which will require the use of a random-effect model to calculate the pooled effect sizes. If sufficient data on the adjusted effect measures are available, we will calculate both pooled adjusted and crude effect sizes (see Sensitivity analysis section). If information on specific opioid-related (opioid dose, opioid formulation and treatment duration) and individual-level characteristics is available, we will conduct a subgroup analysis and will report group-specific effect estimates. The results of the meta-analysis will be presented as forest plots. If data are insufficient to conduct a meta-analysis for one of the objectives, we will use a narrative approach to data synthesis.

### Sex-based and gender-based analysis

Integrating sex and gender is of crucial importance to our study as both variables exhibit multidirectional effects and can be confounders or effect modifiers (see figure 1). We will apply a broad theoretical and empirical framework to understand the development of *IOU*s and the underlying mechanisms, integrating up-to-date sex and gender, pain and addiction literature. Thus, rather than focusing on the artificially binary categories such as male/female (for sex) or man/woman (for gender), we will take the real-life complexity of these characteristics into consideration. Variables from studies that mention ‘sex’, ‘biological sex’, ‘sex assigned at birth’, ‘male and female’ and similar binary terminology will be treated in the category of sex. The rest of the studies that mention gender-related terminology such as ‘man and woman’, ‘transgender’, ‘gender fluid’, ‘gender nonbinary’, two-spirit (Indigenous), etc, will be assigned to the gender variable. The authors of the primary studies will be contacted for clarifications and to obtain missing data on sex and gender categories, and their responses will be thoroughly documented. We will stratify our analysis by sex/gender categories and will report sex-specific or gender-specific effect measures separately. We will ensure inclusion of sex-specific and gender-specific effect measure estimates in the discussion, as well as the issue of missing non-binary data.

### Publication bias, confounding, sensitivity analysis and quality of cumulative evidence

Publication bias will be assessed examining funnel plots for each outcome, for which more than 10 studies will be included in the meta-analysis.101 

#### Confounding

Sex/gender, history of opioid use, use of other immunosuppressive medications, etc, may have confounding or effect-modifying effects on the association between opioid use and risk of infectious outcomes (see figure 1). As our pilot search showed, most studies use an observational design and thus may be prone to confounding by indication bias. For example, it may seem that patients prescribed opioids are likely to have a more severe disease than persons not prescribed opioids, and the more severe disease may be an independent risk for infections. Indeed, this scenario is possible, but not unique. Disease severity is not always reflective of the analgesia requirements. For example, when compared with controls, patients who sustained small burns and those with the largest burn surfaces were, respectively, 1.73 (95% CI 1.20 to 2.49) and 1.02 (95% CI 0.71 to 1.46) times more likely99 to receive opioids. From our clinical experience and the literature, the decision to prescribe opioids is multifold. Moreover, most public insurances in Canada cover pharmacological (eg, opioid) therapy and frequently do not cover non-pharmacological treatments for CP. This makes opioids an ultimate choice for the poor, not working (eg, students, elderly) and marginalised populations in Canada. Furthermore, the initial doses in opioid-naïve patients will be lower than among patients taking opioids chronically. Recently, there is an increasing emphasis on anaesthesia protocols to reduce reliance on opioid analgesics.121 122 In addition, CP literature identifies depression,123 124 anxiety and pain catastrophising125 as drivers of opioid dose escalation and chronicity of use. A history of sexual abuse in men and a family and personal history of other substance misuse/use disorders are known risk factors126 for problematic opioid use in the future. The attempts to account for the complexity and known confounders, effect modifiers and important covariates will be made in the analysis. In case these data will be missing from the primary studies, the authors will be contacted. If sufficient data on the important covariates are identified, a subgroup analysis will be conducted and the subgroup-specific effect estimates will be reported. Epidemiological biases that can lead to overestimations/underestimations of effect sizes or spurious associations will be discussed as study limitations.

#### Sensitivity analysis

To assess the robustness of our results on each outcome of interest, we will perform sensitivity analyses. First, the pooled effect size estimation will be repeated by including only studies with a low risk of bias, and the results will be compared with the main analysis. Second, we will compare the pooled effect estimates from randomised controlled trials and observational studies. Then, we will evaluate the possible effect of covariates included in the calculation of adjusted effect sizes in the original studies on the pooled effect size. For this, we will estimate the pooled crude effect size for each outcome of interest using crude (non-adjusted) effect sizes for separate studies, if available. The effect estimates will be compared with the adjusted effect estimates obtained in the main analysis.

The Grading of Recommendations Assessment, Development and Evaluation127 framework will be used in the assessment of the quality of cumulative evidence for each outcome of interest. A certainty rating (very low, low, moderate or high) will be assigned.

### Patient and public involvement

Two patient representatives will be part of the SR study team. We will report their contribution in the resulting SR manuscript. As SR results are available, we will organise downstream deliberative dialogue groups with patients, care providers and decision-makers to develop the most optimal ways for knowledge uptake and implementation across clinical settings in Canada, USA, Israel, Germany and other European countries.

### Ethics and dissemination

This review is based on already published literature and thus no ethics review is requested. The results will be published, presented at conferences and discussed in deliberative dialogue groups.

### Timeline for review

At the time of resubmission of our manuscript, we had already started database searches.

### Supplementary data

[[bmjopen-2023-083791supp001.pdf]](pending:yes) 

## Ethics statements

### Patient consent for publication

Not required.

## Footnotes

*   Contributors IK: conceptualisation, writing the original draft, methodology, review and editing; guarantor of the study and accepts full responsibility for the finished work and/or the conduct of the study, has access to the data and controls the decision to publish. MGP, MC: methodology, review and editing. YS, MB-S, BL, MJE: review and editing. SP: conceptualisation, methodology, review and editing.

*   Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

*   Competing interests MGP is supported by the Junior-2 Salary Award from Fonds de recherche du Québec - Santé (FRQS). MJE holds a James McGill Professor Award from McGill University. BL is supported by two career awards: Senior Salary Award from the FRQS and LE 250 from the Quebec Ministry of Health for Researchers in Family Medicine. He also holds a Canadian Institutes of Health Research Strategy for Patient-Oriented Research Mentorship Chair in Innovative Clinical Trials for HIV Care. He has received research support, consulting fees and speaker fees from ViiV Healthcare, Merck and Gilead.

*   Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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