The Incidences of Metabolic Syndrome Complications during Chronic HIV-Antiretroviral Treatment, a Focus on Selected Regimens: A Systematic Review and Meta-Analysis Protoc

Mlindeli Gamede^1*, Mbulelo Aubrey Sosibo² and Mluleki Luvuno^2
*Correspondence: Mlindeli Gamede, Department of Physiology, University of Pretoria, Gauteng, South Africa, Tel: 782075704, Email:

Keywords

Metabolic disease • Metabolic syndrome • Diabetes mellitus • Antiretroviral therapy • HIV antiretroviral regimens • CD4 count and viral load

Introduction

Metabolic Syndrome (MS) is a group of disorders that are associated with metabolisms such as Insulin Resistance (IR), central obesity, hypertension, dyslipidemia, non-alcoholic fatty liver diseases, and Type Two Diabetes Mellitus (T2DM) [1]. The pathogenesis of these conditions can be attributed to factors such as unhealthy lifestyles, genetic susceptibility, and chronic drug treatments (drug-induced metabolic disorders) [2-4]. Sub-Saharan Africa is the region with the highest burden of HIV infections in the African continent and across the world [5]. During the year 2017, Sub-Saharan Africa had about 75% of the world’s HIV related deaths, 65% of the world’s new infections, and 71% of people living with HIV. Globally, above 60% of people that are living with HIV are in Antiretroviral Treatment (ART), and the Eastern and Southern African regions had about 67% of those individuals on ART [6,7]. This makes the sub-Saharan African region to be the one with the highest population on ART. The global response to the HIV pandemic includes encouraging all individuals with HIV infection to take ART regardless of their viral load or CD4 count. Hence, South Africa has recently adopted the “test and treat” strategy [8]. This strategy aims to identify at least 90% of all infected individuals, 90% in enrolling diagnosed individuals in ART, and 90% in HIV viral suppression in all ART receiving patients [9]. However, some ART regimes such as Highly Active Antiretroviral Therapy (HAART) have been previously associated with metabolic complications including hyperlipidemia and reduction in circulating adipokines [10]. Hence, the recent guidelines for ART initiation involve the screening of non-communicable diseases including diabetes, hypertension, and epilepsy [11]. The dispensation of ART can be done in any of the three regimens namely first, second, and third-line regimens respectively. This depends on the clinical scenario presented by the patient during enrolment or if the other lower regimen fails to suppress the viral load. Table 1 indicates the drugs and combinations of drugs that make up the first-and second-line ART regimens as per the World Health Organization (WHO). Among these ART regimens (first and second-line) the profile of the risk factors and level of the risk of developing metabolic complications remain unclear. This review is aimed at compiling the data about metabolic syndrome complications associated with recently approved ART. Furthermore, this review will also compare the prevalence of these complications between the first-line and second-line Antiretroviral (ARV) regimens [12]. The findings of this review may indicate if the newly formulated ART is associated with the onset of metabolic syndrome complication. This will be determined by the prevalence of these complications in patients that have been chronically receiving ART in the revised formulations. This information might alert the clinicians to recommend lifestyle modification for patients that are initiated in the regimes. Lifestyle modifications include increasing physical activity, quitting alcohol, and healthy eating habits. These interventions might improve the quality of life for the patients on ART and reduce the risks of the development of other complications such as kidney and heart conditions.

Table 1. Drugs in ART regimen one and regimen two recommended by a world health organization.

Review questions

The purpose of this protocol is to elaborate on the design and the procedures that will be used in the proposed systematic review to answer the following research questions:

Primary: What is the association between chronic ARV regimens and the onset of metabolic syndrome complications?

Secondary: Which ART regimen that most associated with metabolic syndrome complication between regimen one and two.

Literature Review

The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were used to formulate this protocol, which outlines the methods that will be used for the proposed systematic review and meta-analysis. Furthermore, this protocol has been registered with PROSPERO.

Eligibility criteria

The studies that are reporting the presence of metabolic and cardiometabolic complications in patients that are on ART, particularly the first and second regimens will be eligible for selection and the criteria for metabolic syndrome is narrated in Table 2.

Table 2. Criteria for metabolic syndrome that is going to be used in the envisage systematic review.

Study design eligible

Primary epidemiological observational study designs such as cross-sectional cohort and case control studies. The intervention studies will also be eligible for selection due to the availability of the data from non-treated control. Animal research studies will not be eligible for selection due to the uncertainty of chronic exposure to ARV medication.

Participants eligible

Population from the region of sub-Saharan Africa aged 18 years and, that have been on ARV medication for more than five years. The participants that have reported a history of metabolic syndrome complications will be excluded due to increased risk of bias.

Exposures eligible

ARV medication for HIV, regimen one and regimen two.

Outcome measures eligible

The outcome reports on the effects of any of the drugs used in the making of regimen one and regimen two on the metabolic and cardiovascular systems. The outcome of interest is the metabolic and cardiovascular abnormalities in the selected population including Fasting plasma glucose; Oral Glucose Tolerance Test (OGTT); random plasma glucose; HOMA index; body mass index; lipid profile (LDL-C, HDL-C, TGs); blood pressure.

Data representation

The forest plots, odds of ratio, and Standard Error of a Mean (SEM) will be used to present data.

Patient and public involvement

This study does not involves the patients and public.

Information sources

Search engines or database: PubMed, Google Scholar, Medline, Science direct, and Embase Database.

Website: clinical info.hiv.gov.

Organizations: World health organization, UNAIDS, center for aids research, UC San Diego treatment action campaign, centers for disease control and prevention, governments department of health reports

Search strategy

Keywords/phrases: ART regimen one, ART regimen two, ARV fixe dose combination, ARV induced metabolic syndrome, ARV induced metabolic syndrome, ARV induced glucose intolerance, ARV induced cardiometabolic diseases, and ARV induce energy dysregulation

Selection process

The selection process show in Table 3.

Table 3. Inclusion and exclusion criteria.

Results and Discussion

Data extraction process

The criteria that will be used to extract data will include the study identifiers, study design, exposure, and outcome information. Study identifiers will include the author names, study title, publication type and date, publication details (journal name, volume, issue, and page numbers), and the location where the research was being conducted, identified by the address of the corresponding authors. The data extraction will also be guided by the details of the participants i.e. the age and gender of the participants at the time of research. The exposure extracted will include the name of the drug studied, the size of the population, and the report about either metabolic or cardiovascular complications post chronic exposure to the drug. At least one of the targeted parameters must be present in the publication for the data to be extracted.

Two reviewers will independently review every record and report retrieved by the search strategy independently, while the third reviewer will serve as arbitrator where there are disagreements between the two reviewers. The publications that will be selected for the screening process will have to qualify through the criteria. The selection of eligible studies will be done in two folds, the first being the screening of the record and reports using the titles and abstracts using the questions in Table 4. The records that will meet the inclusion criteria will be taken forward to the second fold. The second fold will be a full article screening; this will be based on the questions in Table 5.

Table 4. The screening process, assessing the articles one by one, pre-analysis.

Table 5. The final step of screening the articles.

Data collection process

Selection-the research team will select studies and extract data following this process:

• Studies title screening of database search results by the primary investigator.
• Abstract screening of listed eligible studies for the study’s population, exposure, comparator, and outcome settings using a designed Google form screening tool checklist. Any unresolved screening will be resolvedby the third reviewer.
• Eligible abstract screened studies will be screened for full article screening by two reviewers.
• Data extraction will be done for eligible full articles by two reviewers independently, one person for data extraction, and the second person will verify at least 50% of studies for general characteristics information and 100% of studies regarding outcomes data.

Comparator, control: The population within the same age group, HIV positive or negative but not on ARV treatment and without a history of metabolic syndrome complications. However, data from HIV positive patients will be specified in the review.

Risk of bias assessment

The quality assessment of the review will involve:

• The researchers will assess the potential of the studies to be included and the third reviewer will assess the appropriateness of methods and assess the risk of bias using the Hoy, et al. tool.
• The study will include studies that are published in English and French language, this will improve the robustness of the study and will allow for the inclusion of francophone African countries. The French study publications that are eligible for the study will be translated to English by a Google translator.
• The minimum sample size for included studies will be calculated to differentiate estimates with good precision using the Clapper- Pearson confidence interval formula.
• Publication bias: If there are >=10 studies in the meta-analysis, we will further investigate publication bias using funnel plots and Egger`s test. If asymmetry is presently based on visual assessment, we will perform exploratory analyses to investigate and adjust this using trim and/or fill analysis.
• Heterogeneity: We will assess statistical heterogeneity in our meta-analysis using the I-squared statistic. If the I-squared is greater than 50% we will be regarded as substantial heterogeneity.

Strategy for data synthesis: We will calculate 95% confidence intervals for all discrete and co-morbid metabolic syndrome, diabetes, and hypertension prevalence measures using the Clopper-Pearson method.

Test for heterogeneity will be conducted using X² and I² me.

A random effects meta-analysis estimate will be used to analyze the estimated prevalence data that will be pooled, to estimate the mean of the distribution of effects. A forest plot will be generated displaying prevalence with the corresponding confidence interval for each included study and the overall random effects pooled estimate with its confidence interval.

Conclusion

For studies with several risk estimates of these conditions; the multivariable regression model risk will be chosen. Data from any article providing multiple study outcome measures for different population subgroups (HIV positive and negative population) will be extracted as separate studies and treated as separate datasets in the analysis.

Conflicts of Interest

None.

Author Contribution

Dr. Mlindeli Gamede was involved in conceptualizing, designing of the work, the acquisition, analysis, interpretation of data, drafted the manuscript and substantively revised the manuscript. Mr. Aubrey Sosibo was involved in the conception, design of the work, the acquisition of data Dr. Mluleki Luvuno was involved in conceptualizing, design of the work, analysis, interpretation of data, and substantively revised the manuscript. The whole team is involved in writing the actual systematic review and meta-analysis.

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