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.
A manual search will be also done for additional articles that may not be included on the aforementioned platforms. The following search terms will be used: ‘‘Dolutegravir’’, ‘‘Antiretroviral’’, ‘‘Safety’’, ‘‘Adverse events’’, ‘‘Human Immunodeficiency Virus’’, ‘‘Adverse effects’’, ‘‘Acquired Immunodeficiency Syndrome’’, ‘‘Adverse drug reactions’’, and ‘‘Adolescent’’. These terms will be used in different combinations with boolean operators for the listed databases.
Criteria for Considering Studies for this Review
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.
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 socio-demographics.
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 first-line treatment of HIV.
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.
Studies that reported on DTG ADR outcomes not limited to physical symptoms, hospitalizations, deterioration in organ function (hepatic or renal function), Immune Reconstitution Inflammatory 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.
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 efficacy . This may affect the ADR profile of DTG.
Studies that recruited patients with severe hepatic impairment. Hepatic toxicity has been reported without previous hepatic disease in some patients . Therefore, studies conducted on these patients would potentially have biased outcomes regarding the DTG ADR profile.
Animal studies will be excluded because the reviewers are interested in clinically relevant study findings 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 identified through the screening of titles and abstracts after duplicated studies have been identified 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 flow diagram illustrating the various stages of the review, and results obtained will be presented.
Data Extraction and Management
After the selection of the final study sample, a data extraction form (see additional file 1) will be used to extract data. The form will contain the following sections:
Table 1: Study Characteristics - Lead author, year, study design, sample size, study setting/country, details of DTG/antiretroviral drug regimen/combination/intervention, duration of treatment, comparator, and funding source.
Table 2: Summary of Findings - Outcomes (any adverse drug reactions/events, most common ADRs/events, ADRs/events requiring discontinuation, number of ADRs/adverse events leading to death).
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 clarification 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 . Assessment is arranged into several domains that bias may be introduced . A judgement/conclusion of a high risk of bias in any domain consequently means the whole study has a high risk of bias .
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 case-control or cohort studies . 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 .
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.
Adverse drug reactions will be classified 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 .
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 findings. Also, findings on the co-administration of DTG with other drugs, and how DTG use in different regimens affects adverse drug reactions will be presented. The findings 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 sub-group analysis will be performed.