Dolutegravir Reported Adverse Drug Reactions: A Systematic Review Protocol

Background: Until recently, the rst-line regimen for the management of Human Immunodeciency Virus (HIV) was Tenofovir (TDF)-Emtricitabine (FTC) and Efavirenz (EFV). However, the use of EFV has now been limited due to adverse neurosensory effects and a low genetic barrier to resistance. This regimen has been replaced by the Dolutegravir (DTG)-based regimen since DTG has a high genetic barrier to resistance. Studies have reported a higher risk of Immune Reconstitution Inammatory Syndrome (IRIS), weight gain, insomnia, and neural tube defects amongst people who received DTG. This review aims to assess the adverse drug reaction (ADR) prole of Dolutegravir by identifying and classifying Dolutegravir-associated adverse drug reactions. Methods: Studies will be identied from an electronic database search. Studies that are potentially eligible will be selected through screening. Two team members will independently screen all citations, full-text articles, and abstract data; conicts will be resolved through discussion. The (PRISMA-P) ow diagram that outlines all phases of screening and reasons for exclusion will be used during the selection process. After the selection of the nal study sample, a data extraction form will be used as a collection tool. The data will be entered into Cochrane Collaboration Review Manager (RevMan 5.2) for storage and management. All the evidence gathered will be assessed for bias through the use of the Risk of Bias tool RoB 2.0 of Cochrane Collaboration. Reported ADRs will then be classied. We will also provide data for the effect of different demographic factors on ADRs as well as the effects of co-administration of DTG with other drugs on ADRs. We will additionally provide information on how Dolutegravir use in different regimens affects the ADRs. Results from the review will be summarized quantitatively through meta-analysis. A forest plot will be used to present results from the meta-analysis. Conclusion: A review of existing studies will aid in establishing the safety prole of this drug. This review will make signicant contributions to healthcare practice. It will aid in improving prescribers' and dispensers’

Until recently, the regimen recommended for the rst-line combination treatment of HIV was Tenofovir (TDF)-Emtricitabine (FTC) and Efavirenz (EFV) also known as TEE [18]. However, the consistent use of EFV due to its adverse neurosensory effects and low genetic barrier from the drug-resistance mutations has become a limitation for its use [22]. According to the latest antiretroviral therapy (ART) clinical guidelines, the Efavirenz-based regimen has been replaced by the Dolutegravir (DTG)-based regimen due to its favourable pro le of maintained viral suppression and immunological recovery [25].
The recommended regimen for the primary management of HIV is Tenofovir (TDF)-Lamivudine (3TC)-Dolutegravir (DTG) also known as TLD [18]. DTG is cheap, has an increased genetic barrier to resistance, and is accessible as a xed-combination pill, and hence was introduced as the preferred rst-line therapy for HIV by the WHO in 2018 [28]. However, the administration of DTG at conception could result in neuraltube defects in infants and must therefore be used with caution in pregnant women. The drug is also known to increase the risk of insomnia and obesity [28]. There is more evidence that the risks of weight gain, insomnia, Immune Reconstitution In ammatory Syndrome (IRIS), and neural tube defects amongst patients receiving DTG are increased [3]. These adverse drug reactions (ADRs) are common and easily identi able. A global investigation into DTG ADRs is important in understanding how South Africa can manage a relatively new drug on the HIV regimen. These adverse effects have thus resulted in the WHO making its use conditional and recommended that DTG patients be closely monitored.
A review of the evidence from existing studies that evaluated the safety pro le of DTG is relevant in promoting pharmacovigilance activities. Therefore, this proposed review aims to assess the global ADRs pro le of DTG through: 1. Identi cation and classi cation of DTG-associated ADRs.
2. Establishment of the safety and e cacy of DTG in the therapy of HIV with an emphasis on pregnant women.
3. Identi cation and categorization of the demographic factors associated with DTG ADRs.

Protocol and Registration
The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines were followed in the design of this review protocol. The review protocol was registered with the Open Science Framework (OSF) on the 2nd of December 2020 (doi.org/10.17605/OSF.IO/Z9YAF). If there are any protocol amendments, a description of the change and the rationale will be presented in the main review.

Data Source and Search Strategy
The following databases will be explored from January 2010 to date for studies: Scopus, Web of Science, PubMed, Embase, Vigiacess, Cochrane Clinical trials registry, National institutes for health Clinical Trials Registry, and Cochrane Library.

Study Designs
Studies that will be included in the review will not be limited to randomized clinical trials (RCTs), non-RCTs, cohorts, and case-controls. Systematic reviews and other forms of reviews will be excluded.

Patients (Population)
Studies that reported on DTG ADRs in males and females aged ≥ 18 years will be included. There will be no restrictions regarding ethnicity, participants' language, country of origin, and other sociodemographics.

Interventions
We will include studies that investigated the safety of DTG either alone or in combination with other ARVs. Of particular interest is TLD, which was introduced by the WHO in 2018 as it is currently the only regimen with DTG being prescribed for rst-line treatment of HIV.

Comparators
The team of reviewers will include studies that compared the DTG-containing regimens with previously recommended regimens. Of particular interest is the combination that was just downgraded: TEE.

Outcomes
Studies that reported on DTG ADR outcomes not limited to physical symptoms, hospitalizations, deterioration in organ function (hepatic or renal function), Immune Reconstitution In ammatory Syndrome (IRIS), deaths, and the discontinuation of therapy.
The outlines outcomes will be assessed for all included studies. They will be grouped according to treatment periods. This will assist in assessing the short and long-term effects of DTG.

Exclusion Criteria
Studies exclusively in children less than 18 years. Studies that were conducted in patients who were co-infected with tuberculosis and were being managed with rifampicin. This exclusion is because DTG is a substrate for Cytochrome-P450-3A4 (CYP3A4) and Uridine-diphosphate-glucuronosyltransferase-1A1 (UGT1A1). These enzymes are induced by rifampicin. The co-administration of DTG and rifampicin consequently leads to a reduction of DTG levels in the blood. Doubling the required daily dose of DTG is recommended for appropriate clinical e cacy [4]. This may affect the ADR pro le of DTG.
Studies that recruited patients with severe hepatic impairment. Hepatic toxicity has been reported without previous hepatic disease in some patients [5]. Therefore, studies conducted on these patients would potentially have biased outcomes regarding the DTG ADR pro le.
Animal studies will be excluded because the reviewers are interested in clinically relevant study ndings regarding DTG ADRs.
Studies that were not reported in the English language.

Selection of Studies
Two reviewers/authors will identify studies from the electronic database search and evaluate their eligibility for inclusion in the review. The potentially eligible studies will be identi ed through the screening of titles and abstracts after duplicated studies have been identi ed and removed. Another set of two reviewers will independently perform full-text screening and data extraction. Any disagreements that may arise between the reviewers, during the titles and abstracts screening, and the full-text screening, will be resolved through a discussion with a third reviewer. The agreement between each reviewer pair will be measured and reported by Kappa statistics. A PRISMA ow diagram illustrating the various stages of the review, and results obtained will be presented.

Data Extraction and Management
After the selection of the nal study sample, a data extraction form (see additional le 1) will be used to extract data. The form will contain the following sections:  The data extraction form will be tested to determine its validity and reliability. In the event of unclear or missing information in the selected studies, the corresponding authors of those studies will be contacted via email for clari cation and to provide adequate information. Two independent reviewers will screen the contents of the data extraction form to check for the accuracy and completeness of data. Any observed differences will be resolved by discussion.

Quality assessment and risk of bias
To assess the risk of bias for randomized control studies, the Cochrane Risk of Bias tool will be used. The tool offers a basis for assessing the risk of bias in the outcomes of any randomized trial [27]. Assessment is arranged into several domains that bias may be introduced [27]. A judgement/conclusion of a high risk of bias in any domain consequently means the whole study has a high risk of bias [27].
The Newcastle-Ottawa Scale will be used to assess the risk of bias for nonrandomized studies. Each study will be judged on eight items, categorized into three groups: the selection of the study groups, the comparability of the groups, and the determination of the exposure or outcome of interest for casecontrol or cohort studies [26]. A study can be awarded a maximum of one star for each numbered item within the selection and outcome categories and a maximum of two stars can be given for Comparability [26].
Two reviewers will independently assess the methodological quality of eligible studies and avoid the exclusion of studies based on the methodological quality assessment outcomes. For studies that employed other study designs, the reviewers would adopt an appropriate methodological quality appraisal tool. A third reviewer would serve as an arbiter in instances of disagreement between the independent reviewers.

Data Synthesis
Adverse drug reactions will be classi ed into six types. Dose-related reactions (ARRs at normal or overdose), non-dose-related reactions (eg allergy or anaphylaxis), dose and time-related (due to dose accumulation), time-related (due to prolonged use), withdrawal (effects after stopping the drug), and failure of therapy [6].
We will further group reported ADRs as; The patient/participant was hospitalized due to the reaction.
The patient/participant's life was threatened by the reaction.
The patient/participant's hospitalization time was prolonged due to the reaction.
The reaction caused long-term patient/participant disability.
The reaction did not lead to any of the above but was severe.
The reaction was not severe.
The sociodemographic data of participants of included studies will be synthesized and presented as part of the study ndings. Also, ndings on the co-administration of DTG with other drugs, and how DTG use in different regimens affects adverse drug reactions will be presented. The ndings from the review will be summarized quantitatively, unless otherwise. Homogenous studies will be analysed statistically through a meta-analysis. The lead author will make the entry into Cochrane Collaboration Review Manager (RevMan 5.2), and the second author will check for data entry errors and manage them appropriately.
Results from the meta-analysis will be presented in a forest plot. Where possible, a sensitivity and subgroup analysis will be performed.

Discussion And Conclusions
Globally, more than 38 million people are infected by HIV. Effective antiretroviral therapy with the DTG regimen is available, yet there are safety concerns about the risks of weight gain, insomnia, Immune Reconstitution In ammatory Syndrome (IRIS), and neural tube defects.
Our ndings regarding the overall safety of DTG will be of great signi cance to policy-makers, healthcare providers, and patients. Additionally, we hope to identify gaps in research that may form the basis for future studies of DTG in ART regimens. The results of this study will provide a basis for ongoing medication safety monitoring for Dolutegravir regimens.

Limitations of the review
The reporting quality of some studies may be poor thus affecting the results. Studies may fail to provide a clear de nition of ADRs or report on ADR incidence data. Additionally, studies might not use the same classi cation when reporting ADRs.This might make it di cult to draw an accurate conclusion.

Consent for publication
None.
Availability of data and materials None.

Competing interests
None.

Funding
None.

Authors' contributions
All the authors contributed signi cantly to the conception and development of the manuscript. The listed authors have read the manuscript for scienti c content and have approved the manuscript for publication.